Treatment and prevention of sleep disorders

ABSTRACT

The disclosure relates to methods for treating or preventing a sleep disorder by administering a compound of formula (1)(1), or a compound of formula (1A), (1B), (1C), (1D), (1E), or (1F) to an animal in need of such treatment. In certain embodiments, such compounds effectively treat or prevent a sleep disorder in the animal, while producing reduced side effects compared to previously available compounds.

1. FIELD

The disclosure relates to methods for treating or preventing a sleepdisorder by administering a compound of formula (1), (1A), (1B), or (1C)or a pharmaceutically acceptable salt or solvate thereof, or a compoundof formula (1D), (1E), or (1F) or a solvate thereof to an animal, e.g.,a human, in need of such treatment. In certain embodiments, suchcompounds effectively treat or prevent a sleep disorder in the animal,while producing fewer or reduced side effects compared to previouslyavailable compounds.

2. BACKGROUND

Sleep disorders are widely prevalent world-wide and in the UnitedStates. Under one classification scheme, six broad categories of sleepdisorders have been identified: (i) insomnia, (ii) hypersomnia, (iii)parasomnia, (iv) circadian rhythm sleep-wake disorders, (v)sleep-related breathing disorders, and (vi) sleep movement disorders.Under another classification scheme, ten broad primary categories ofsleep disorders have been identified: (1) insomnia disorder, (2)hypersomnolence disorder, (3) narcolepsy, (4) breathing-related sleepdisorders, (5) circadian rhythm sleep-wake disorders, (6) non-rapid eyemovement (“NREM”) sleep arousal disorders, (7) nightmare disorder, (8)rapid eye movement sleep behavior disorder, (9) restless leg syndrome,and (10) substance/medication-induced sleep disorder. Under eitherscheme, multiple subcategories are recognized within each of the broadcategories.

Insomnia has been defined as the condition, with no obvious cause, ofdifficulty in falling asleep and/or staying asleep. Insomnia is the mostcommon sleep disorder affecting millions of people as either a primaryor comorbid condition. Insomnia has been defined as both a disorder(see, e.g., Espie, “Insomnia: Conceptual Issues in the Development,Persistence and Treatment of Sleep Disorder in Adults,” Ann. ReviewsPsychology 53:215-243 (2002)) and a symptom (see, e.g., Hirshkowitz,“Neuropsychiatric Aspects of Sleep and Sleep Disorders,” Chapter 10 (pp.315-340) in Essentials of Neuropsychiatry and Clinical Neurosciences,Yudofsy et al., eds., 4^(th) Ed., American Psychiatric Publishing,Arlington, Va. (2004)), and this distinction may affect itsconceptualization from both research and clinical perspectives. Whetherinsomnia is viewed as a disorder or a symptom, however, it neverthelesshas a profound effect on the individual and on society. Insomniadisorder results in significant distress and/or functional impairmentsin those who suffer from the condition, underscoring the need forappropriate treatment.

Estimates of the prevalence of insomnia depend on the criteria used inits definition and, more importantly, the population studied. A generalconsensus developed from a number of population-based studies drawingfrom different countries is that approximately 30% of adults report oneor more of the symptoms of insomnia: difficulty initiating sleep,difficulty maintaining sleep, waking up too early and, in some cases,nonrestorative or poor quality of sleep. If the diagnostic criteriainclude perceived daytime impairment or distress as a result of theinsomnia, in 2005 the NIH determined the prevalence of insomnia in theU.S. to be approximately 10%. If insomnia persists for at least onemonth and is not due to another sleep disorder, mental disorder,substance use disorder, or medical condition, the prevalence isapproximately 6%.

Alcohol dependence is a very common substance use disorder worldwide.Alcohol use disorder, defined according to Diagnostic and StatisticalManual of Mental Disorders criteria (DSM-5, 5^(th) Ed., Amer.Psychiatric Publishing, Arlington, Va. (2013)), including all severityclassifications, has a lifetime occurrence of about 29% in the UnitedStates (Grant et al., “Epidemiology of DSM-5 Alcohol Use Disorder,” JAMAPsychiatry 72(8):757-766 (2015)). Additionally, alcohol dependence,classified as a separate condition under the DSM 4^(th) Edition (DSM-IV,4^(th) Ed., Amer. Psychiatric Publishing, Arlington, Va. (1994)) has alifetime occurrence of about 12.5% in the United States (Hasin et al.,“Prevalence, correlates, disability, and comorbidity of DSM-IV alcoholabuse and dependence in the United States,” Arch. Gen. Psychiatry64:830-842 (2007)).

It is known that sleep disorders are more common among alcoholics thanamong non-alcoholics (Brower, “Alcohol's Effects on Sleep inAlcoholics,” Alcohol Res. Health 25(2):110-125 (2001)). For example,Brower discloses, in the general population in the prior 6 months,insomnia affected 18% of alcoholics but only 10% of non-alcoholics andthat rates of insomnia are even higher among patients admitted foralcoholism treatment, ranging from 36% to 72%, depending on samplecharacteristics, the type of sleep-measuring instrument, the amount oftime elapsed since the last drink, and the presence of other disorders.Another reference discloses that 91% of alcoholic participants in asleep study suffered from a sleep disturbance as measured by thewell-accepted Pittsburgh Sleep Quality Index (“PSQI”) (Conroy et al.,“Perception of Sleep in Recovering Alcohol Dependent Patients withInsomnia: Relationship to Future Drinking,” Alcohol Clin. Exp. Res.30(12):1992-1999 (2006)).

Polysomnography (“PSG”) is a multiparametric test used for studyingsleep and for diagnosing sleep disorders. A polysomnography evaluationinvolves the comprehensive measurement and recording of biophysiologicalchanges occurring during sleep. This typically involves, during the timein bed, continuous recording (in the form of a polysomnogram) of thebrain waves (electroencephalogram or EEG), heart rate and rhythm(electrocardiogram or “ECG”), eye movements (electrooculogram or “EOG”),muscle activity and limb movements (electromyogram or “EMG”), bloodoxygen level, breathing pattern and air flow, body position, and snoringand other noises made during sleep. Exclusive of the eyes, EMG typicallyevaluates chin muscle tone, leg movements, chest wall movement, andupper abdominal wall movement.

Existing drugs are known to moderate sleep via a variety of mechanisms.For example, benzodiazepines (e.g., lorazepam, temazepam, triazolam),barbiturates (e.g., phenobarbital, pentobarbital, secobarbital), andso-called “z-drugs” (e.g., zaleplon, zolpidem, zopiclone) all increasesleep by potentiating the action of GABA via action on the GABAareceptor. The benzodiazepines potentiate GABA by increasing thefrequency of chloride channel opening. The barbiturates potentiate GABAby increasing the duration of chloride channel opening. The z-drugs areagonists at the GABAaγ1 subunit. Other existing drugs increase sleep bydifferent mechanisms, for example, ramelteon (ROZEREM) is an agonist forthe two high-affinity G protein-coupled receptors, termed MT₁ and MT₂,in the suprachiasmatic nucleus (“SCN”) while other drugs (e.g.,suvorexant) are orexin receptor antagonists. Many of these existingdrugs are classified as controlled substances under the ControlledSubstances Act and thus carry the risk of abuse and addiction. Forexample, lorazepam, temazepam, triazolam, phenobarbital, zaleplon,zolpidem, zopiclone, and suvorexant are all classified as Schedule IVControlled Substances pursuant to 21 CFR § 1308.14 while pentobarbitaland secobarbital are each classified as Schedule II ControlledSubstances, that is, substances that have a high potential for abusewhich may lead to severe psychological or physical dependence.Cautionary warnings also pertain to certain of these existing drugs. Forexample, the March 2017 prescribing information for zolpidem tartrate(AMBIEN) states that persons with a history of addiction to, or abuseof, alcohol are at increased risk for misuse, abuse and addiction tozolpidem; avoid AMBIEN use in patients with severe hepatic impairment;and persons experiencing insomnia are instructed to advise theirphysician if they have a history of alcohol abuse or addiction and/orhave liver or kidney disease. Still other existing drugs or drug-likesubstances are known to decrease sleep, for example, modafinil,tricyclic antidepressants (e.g., desipramine, protriptyline,trimipramine), selective serotonin reuptake inhibitors (e.g.,citalopram, fluoxetine, paroxetine), norepinephrine reuptake inhibitors(e.g., atomoxetine, maprotiline, reboxetine), and stimulants (e.g.,amphetamine, caffeine).

Identification of the ORL-1 receptor as distinct from the threelong-known major classes of opioid receptors in the central nervoussystem—mu, kappa, and delta—resulted from experimentation on theseopioid receptor classes. The ORL-1 receptor was identified andclassified as an opioid receptor based only on amino acid sequencehomology, as the ORL-1 receptor did not exhibit overlapping pharmacologywith the classic mu opioid receptor. It was initially demonstrated thatnon-selective ligands having a high affinity for mu, kappa, and deltareceptors had low affinity for the ORL-1 receptor. This characteristic,along with the fact that an endogenous ligand had not yet beendiscovered, led to the term “orphan receptor.” See, e.g., Henderson etal., “The orphan opioid receptor and its endogenousligand—nociceptin/orphanin FQ,” Trends Pharmacol. Sci. 18(8):293-300(1997). Subsequent research led to the isolation and structure of theendogenous ligand of the ORL-1 receptor (i.e., nociceptin; also known asorphanin FQ or OFQ), a seventeen amino acid peptide structurally similarto members of the opioid peptide family. For a general discussion ofORL-1 receptors, see Calo' et al., “Pharmacology of nociceptin and itsreceptor: a novel therapeutic target,” Br. J. Pharmacol. 129:1261-1283(2000).

U.S. Pat. Nos. 8,476,271 and 9,145,408 disclose compounds having anaffinity for the ORL-1 receptor.

U.S. Pat. Nos. 7,566,728 and 8,003,669 purport to disclose ORL-1receptor agonist compounds useful for treating circadian rhythm sleepdisorder.

Teshima et al. (“Nonphotic entrainment of the circadian body temperaturerhythm by the selective ORL1 receptor agonist W-212393 in rats,” Brit.J. Pharmacol. 146:33-40 (2005)) describes that the ORL-1 receptoragonist W-212393 may influence circadian entrainment in rats.

Zaveri (“Nociceptin Opioid Receptor (NOP) as a Therapeutic Target:Progress in Translation from Preclinical Research to Clinical Utility,”J. Med. Chem. 59(15):7011-7028 (2016)) reviews recent progress towardsvalidating the NOP system as a therapeutic target.

The present disclosure provides certain ORL-1 receptor modulators usefulfor treating or preventing sleep disorders.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY

In one aspect, the disclosure provides methods for treating a sleepdisorder in an animal comprising administering a therapeuticallyeffective amount of one or more compounds of formula (1), (1A), (1B), or(1C):

or pharmaceutically acceptable salt or solvate thereof, or compounds offormula (1D), (1E), or (1F):

i.e., Compound (1D), Compound (1E), and Compound (1F), respectively, ora solvate thereof, to an animal in need of such treatment. In certainembodiments, such compounds of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or the compounds offormula (1D), (1E), or (1F) or a solvate thereof, effectively treat asleep disorder in the animal, while producing fewer or reduced sideeffects compared to previously available compounds. In certainembodiments, such compounds of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or the compounds offormula (1D), (1E), or (1F) or a solvate thereof, exhibit affinity forthe ORL-1 receptor.

In another embodiment of the disclosure, compositions are disclosedwhich comprise an effective amount of a compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or a compound of formula (1D), (1E), or (1F) or a solvate thereof, and apharmaceutically acceptable carrier or excipient. The compositions areuseful for treating or preventing a sleep disorder in an animal.

In another embodiment of the disclosure, an effective amount of acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, or composition comprising the same, can beused to treat or prevent a sleep disorder including, but not limited toinsomnia (e.g., “adult” insomnia, child insomnia, middle-of-the-nightinsomnia, and short sleeper disorder); hypersomnia (such as insufficientsleep syndrome); circadian rhythm sleep-wake disorder (e.g., delayedsleep-wake phase, advanced sleep-wake phase, irregular sleep-wakerhythm, non-24-hour sleep-wake rhythm, shift work syndrome, and jetlag); an alcohol-induced sleep disorder (e.g., insomnia-typealcohol-induced sleep disorder, daytime sleepiness type alcohol-inducedsleep disorder, parasomnia type alcohol-induced sleep disorder, andmixed type alcohol-induced sleep disorder); insomnia in alcohol usedisorder; a sleep disturbance associated with alcohol cessation (e.g.,insomnia associated with alcohol cessation); or any combination thereof.

In another embodiment of the disclosure, an effective amount of acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, or composition comprising the same, can beused to treat or prevent a sleep disorder including, but not limited toinsomnia (e.g., “adult” insomnia, child insomnia, middle-of-the-nightinsomnia, and short sleeper disorder); hypersomnia (such as insufficientsleep syndrome); circadian rhythm sleep-wake disorder (e.g., delayedsleep-wake phase, advanced sleep-wake phase, irregular sleep-wakerhythm, non-24-hour sleep-wake rhythm, shift work syndrome, and jetlag); or any combination thereof.

In another embodiment of the disclosure, an effective amount of acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, or composition comprising the same, can beused to treat or prevent a sleep disorder including, but not limited to,an alcohol-induced sleep disorder (e.g., insomnia-type alcohol-inducedsleep disorder, daytime sleepiness type alcohol-induced sleep disorder,parasomnia type alcohol-induced sleep disorder, and mixed typealcohol-induced sleep disorder); insomnia in alcohol use disorder; sleepdisturbances associated with alcohol cessation (e.g., insomniaassociated with alcohol cessation); or any combination thereof.

The disclosure can be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments of the disclosure.

4. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a bar chart summarizing the human Sleep Efficiency (“SE”)results in Example 3 for the full analysis population with the standarderror bars as indicated.

FIG. 2 shows a bar chart summarizing the human Latency to PersistentSleep (“LPS”) results in Example 4 for the full analysis population withthe standard error bars as indicated.

FIG. 3 shows a bar chart summarizing the human Wake After Sleep Onset(“WASO”) results in Example 5 for the full analysis population with thestandard error bars as indicated.

FIG. 4 shows a bar chart summarizing the human Total Sleep Time (“TST”)results in Example 6 for the full analysis population with the standarderror bars as indicated.

FIG. 5A shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat wakefulness during the 24 hour period after Day 1 dosing.

FIG. 5B shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat rapid eye movement (“REM”) sleep during the 24 hour period after Day1 dosing.

FIG. 5C shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat non-rapid eye movement (“NREM”) sleep during the 24 hour periodafter Day 1 dosing.

FIG. 6A shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat wakefulness every 3 hours during the 24 hour periodafter Day 1 dosing.

FIG. 6B shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat REM sleep every 3 hours during the 24 hour periodafter Day 1 dosing.

FIG. 6C shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat NREM sleep every 3 hours during the 24 hour periodafter Day 1 dosing.

FIG. 7A shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat wakefulness during the 24 hour period after Day 4 dosing.

FIG. 7B shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat REM sleep during the 24 hour period after Day 4 dosing.

FIG. 7C shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat NREM sleep during the 24 hour period after Day 4 dosing.

FIG. 8A shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat wakefulness every 3 hours during the 24 hour periodafter Day 4 dosing.

FIG. 8B shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat REM sleep every 3 hours during the 24 hour periodafter Day 4 dosing.

FIG. 8C shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat NREM sleep every 3 hours during the 24 hour periodafter Day 4 dosing.

FIG. 9A shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat wakefulness during the 24 hour period after Day 7 dosing.

FIG. 9B shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat REM sleep during the 24 hour period after Day 7 dosing.

FIG. 9C shows a graph of the effects of 30 mg/kg/day of Compound (1D) onrat NREM sleep during the 24 hour period after Day 7 dosing.

FIG. 10A shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat wakefulness every 3 hours during the 24 hour periodafter Day 7 dosing.

FIG. 10B shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat REM sleep every 3 hours during the 24 hour periodafter Day 7 dosing.

FIG. 10C shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat NREM sleep every 3 hours during the 24 hour periodafter Day 7 dosing.

FIG. 11A shows a graph of the effects of 30 mg/kg/day of Compound (1D)on rat wakefulness during the 24 hour period on Day 8.

FIG. 11B shows a graph of the effects of 30 mg/kg/day of Compound (1D)on rat REM sleep during the 24 hour period on Day 8.

FIG. 11C shows a graph of the effects of 30 mg/kg/day of Compound (1D)on rat NREM sleep during the 24 hour period on Day 8.

FIG. 12A shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat wakefulness every 3 hours during the 24 hour periodon Day 8.

FIG. 12B shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat REM sleep every 3 hours during the 24 hour periodon Day 8.

FIG. 12C shows a bar chart summarizing the effects of 30 mg/kg/day ofCompound (1D) on rat NREM sleep every 3 hours during the 24 hour periodon Day 8.

FIG. 13A shows a graph of the effects of 10 mg/kg of Compound (1D) onrat wakefulness during the 24 hour period after dosing.

FIG. 13B shows a graph of the effects of 10 mg/kg of Compound (1D) onrat REM sleep during the 24 hour period after dosing.

FIG. 13C shows a graph of the effects of 10 mg/kg of Compound (1D) onrat NREM sleep during the 24 hour period after dosing.

FIG. 14A shows a bar chart summarizing the effects of 10 mg/kg ofCompound (1D) on rat wakefulness every 3 hours during the 24 hour periodafter dosing.

FIG. 14B shows a bar chart summarizing the effects of 10 mg/kg ofCompound (1D) on rat REM sleep every 3 hours during the 24 hour periodafter dosing.

FIG. 14C shows a bar chart summarizing the effects of 10 mg/kg ofCompound (1D) on rat NREM sleep every 3 hours during the 24 hour periodafter dosing.

FIG. 15A shows a graph of the effects of 100 mg/kg of Compound (1D) onrat wakefulness during the 24 hour period after dosing.

FIG. 15B shows a graph of the effects of 100 mg/kg of Compound (1D) onrat REM sleep during the 24 hour period after dosing.

FIG. 15C shows a graph of the effects of 100 mg/kg of Compound (1D) onrat NREM sleep during the 24 hour period after dosing.

FIG. 16A shows a bar chart summarizing the effects of 100 mg/kg ofCompound (1D) on rat wakefulness every 3 hours during the 24 hour periodafter dosing.

FIG. 16B shows a bar chart summarizing the effects of 100 mg/kg ofCompound (1D) on rat REM sleep every 3 hours during the 24 hour periodafter dosing.

FIG. 16C shows a bar chart summarizing the effects of 100 mg/kg ofCompound (1D) on rat NREM sleep every 3 hours during the 24 hour periodafter dosing.

FIG. 17A shows a graph of the effects of 10 mg/kg zolpidem on ratwakefulness during the 24 hour period after dosing.

FIG. 17B shows a graph of the effects of 10 mg/kg zolpidem on rat REMsleep during the 24 hour period after dosing.

FIG. 17C shows a graph of the effects of 10 mg/kg zolpidem on rat NREMsleep during the 24 hour period after dosing.

FIG. 18A shows a bar chart summarizing the effects of 10 mg/kg zolpidemon rat wakefulness every 3 hours during the 24 hour period after dosing.

FIG. 18B shows a bar chart summarizing the effects of 10 mg/kg zolpidemon rat REM sleep every 3 hours during the 24 hour period after dosing.

FIG. 18C shows a bar chart summarizing the effects of 10 mg/kg zolpidemon rat NREM sleep every 3 hours during the 24 hour period after dosing.

FIG. 19A shows a graph of the human plasma concentration of Compound(1D) on a linear scale versus linear time after the administration atthree different single doses.

FIG. 19B shows a graph of the human plasma concentration of Compound(1D) on a logarithmic scale versus linear time after the administrationat three different single doses.

5. DETAILED DESCRIPTION

The invention includes the following:

(1) A method for treating or preventing a sleep disorder, comprisingadministering to an animal in need thereof a therapeutically effectiveamount of a compound of Formula (1)

or a pharmaceutically acceptable salt thereof.

(2) The method of the above (1), wherein the compound is a compound ofFormula (1A)

or a pharmaceutically acceptable salt thereof.

(3) The method of the above (1), wherein the compound is a compound ofFormula (1B)

or a pharmaceutically acceptable salt thereof.

(4) The method of any one of the above (1)-(3), wherein the compound isa compound of Formula (1C)

or a pharmaceutically acceptable salt thereof.

(5) The method of any one of the above (1)-(4), wherein the compound isa compound of Formula (1D)

(6) The method of any one of the above (1)-(4), wherein the compound isa compound of Formula (1E)

(7) The method of any one of the above (1)-(4), wherein the compound isa compound of Formula (1F)

(8) The method of any one of the above (1)-(7), wherein the sleepdisorder is an insomnia condition, a hypersomnia condition, a circadianrhythm sleep-wake disorder, an alcohol-induced sleep disorder, or anycombination thereof.

(9) The method of the above (8), wherein the alcohol-induced sleepdisorder is insomnia-type alcohol-induced sleep disorder, daytimesleepiness type alcohol-induced sleep disorder, parasomnia typealcohol-induced sleep disorder, mixed type alcohol-induced sleepdisorder, insomnia in alcohol use disorder, a sleep disorder associatedwith alcohol cessation, insomnia associated with alcohol cessation, orany combination thereof.

(10) The method of the above (9), wherein the alcohol-induced sleepdisorder is treated.

(11) The method of the above (9), wherein the alcohol-induced sleepdisorder is prevented.

(12) The method of any one of the above (1)-(8), wherein the sleepdisorder is an insomnia condition, a hypersomnia condition, a circadianrhythm sleep-wake disorder, or any combination thereof.

(13) The method of the above (12), wherein the insomnia condition isinsomnia, child insomnia, middle-of-the-night insomnia, short sleeperdisorder, or any combination thereof.

(14) The method of the above (13), wherein the insomnia condition istreated.

(15) The method of the above (13), wherein the insomnia condition isprevented.

(16) The method of the above (8) or (12), wherein the hypersomniacondition is insufficient sleep syndrome.

(17) The method of the above (16), wherein the hypersomnia condition istreated.

(18) The method of the above (16), wherein the hypersomnia condition isprevented.

(19) The method of the above (8) or (12), wherein the circadian rhythmsleep-wake disorder is delayed sleep-wake phase, advanced sleep-wakephase, irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shiftwork syndrome, jet lag, or any combination thereof.

(20) The method of the above (19), wherein the circadian rhythmsleep-wake disorder is treated.

(21) The method of the above (19), wherein the circadian rhythmsleep-wake disorder is prevented.

(22) The method of any one of the above (1)-(21), wherein sleepefficiency of an animal administered a single daily dose of the compoundor a pharmaceutically acceptable salt thereof on two consecutive days isat least about 1.10 times the sleep efficiency of an animal administereda placebo.

(23) The method of any one of the above (1)-(22), wherein latency topersistent sleep of an animal administered a single daily dose of thecompound or a pharmaceutically acceptable salt thereof on twoconsecutive days is at most about 0.65 times the latency to persistentsleep of an animal administered a placebo.

(24) The method of any one of the above (1)-(23), wherein wake aftersleep onset (WASO) of an animal administered a single daily dose of thecompound or a pharmaceutically acceptable salt thereof on twoconsecutive days is at most about 0.50 times the WASO of an animaladministered a placebo.

(25) The method of any one of the above (1)-(24), wherein administrationof the compound or a pharmaceutically acceptable salt thereof is by atleast one route selected from oral, parenteral, intravenous,intramuscular, buccal, gingival, sublingual, intraocular, transdermal,and transmucosal.

(26) The method of the above (25), wherein administration of thecompound or pharmaceutically acceptable salt thereof is by oral,sublingual, gingival, or buccal administration.

(27) The method of the above (25), wherein administration of thecompound or pharmaceutically acceptable salt thereof is by oral orsublingual administration.

(28) The method of any one of the above (1)-(27), wherein the dosage ofthe compound or pharmaceutically acceptable salt thereof is from about0.003 mg/kg/day to about 100 mg/kg/day based on the body weight of theanimal administered the dosage.

(29) The method of any one of the above (25)-(28), wherein the dosage ofthe compound or pharmaceutically acceptable salt thereof is from about0.003 mg/kg/day to about 10 mg/kg/day based on the body weight of theanimal administered the dosage.

(30) The method of any one of the above (25)-(29), wherein the dosage ofthe compound or pharmaceutically acceptable salt thereof is from about0.003 mg/kg/day to about 5 mg/kg/day based on the body weight of theanimal administered the dosage.

(31) The method of any one of the above (25)-(30), wherein the dosage ofthe compound or pharmaceutically acceptable salt thereof is from about0.003 mg/kg/day to about 1.0 mg/kg/day based on the body weight of theanimal administered the dosage.

(32) The method of any one of the above (25)-(31), wherein the dosage ofthe compound or pharmaceutically acceptable salt thereof is from about0.003 mg/kg/day to about 0.15 mg/kg/day.

(33) The method of any one of the above (25)-(32), wherein the dosage ofthe compound or pharmaceutically acceptable salt thereof is from about0.010 mg/kg/day to about 1.0 mg/kg/day.

(34) The method of any one of the above (25)-(33), wherein the dosage ofthe compound or pharmaceutically acceptable salt thereof is from about0.010 mg/kg/day to about 0.10 mg/kg/day.

(35) The method of any one of the above (1)-(27), wherein the singledaily human dose of the compound or pharmaceutically acceptable saltthereof is from about 0.05 mg to about 50 mg.

(36) The method of the above (35), wherein the single daily human doseof the compound or pharmaceutically acceptable salt thereof is fromabout 0.10 mg to about 15 mg.

(37) The method of the above (35) or (36), wherein the single dailyhuman dose of the compound or pharmaceutically acceptable salt thereofis from about 0.2 mg to about 6.0 mg.

(38) The method of any one of the above (1)-(4) and (8)-(37), whereinthe free base of the compound is administered.

(39) The method of any one of the above (1)-(37), wherein apharmaceutically acceptable salt of the compound is administered.

(40) The method of any one of the above (1)-(6), (8)-(37), and (39),wherein the pharmaceutically acceptable salt is a hydrochloric acidsalt, a p-toluenesulfonic acid salt, a sulfate salt, or a phosphoricacid salt.

(41) The method of any one of the above (1)-(5), (8)-(37), (39), and(40), wherein the pharmaceutically acceptable salt is ap-toluenesulfonic acid salt.

(42) The method of the above (41), wherein the pharmaceuticallyacceptable salt is the mono-tosylate salt.

(43) Use of the compound or a pharmaceutically acceptable salt thereofas defined in any one of the above (1)-(4), (6), (7), and (38)-(42) orthe compound as defined in the above (5) in the preparation of amedicament for the treatment or prevention of a sleep disorder.

(44) The use of the above (43), wherein a sleep disorder is treated.

(45) The use of the above (43), wherein a sleep disorder is prevented.

(46) The use of any one of the above (43)-(45), wherein the sleepdisorder is an insomnia condition, a hypersomnia condition, a circadianrhythm sleep-wake disorder, an alcohol-induced sleep disorder, or anycombination thereof.

(47) The use of the above (46), wherein the sleep disorder is analcohol-induced sleep disorder which is insomnia-type alcohol-inducedsleep disorder, daytime sleepiness type alcohol-induced sleep disorder,parasomnia type alcohol-induced sleep disorder, mixed typealcohol-induced sleep disorder, insomnia in alcohol use disorder, asleep disorder associated with alcohol cessation, insomnia associatedwith alcohol cessation, or any combination thereof.

(48) The use of the above (46) or (47), wherein the alcohol-inducedsleep disorder is insomnia-type alcohol-induced sleep disorder.

(49) The use of the above (46) or (47), wherein the alcohol-inducedsleep disorder is daytime sleepiness type alcohol-induced sleepdisorder.

(50) The use of the above (46) or (47), wherein the alcohol-inducedsleep disorder is parasomnia type alcohol-induced sleep disorder.

(51) The use of the above (46) or (47), wherein the alcohol-inducedsleep disorder is mixed type alcohol-induced sleep disorder.

(52) The use of the above (46) or (47), wherein the alcohol-inducedsleep disorder is insomnia in alcohol use disorder.

(53) The use of the above (46) or (47), wherein the alcohol-inducedsleep disorder is a sleep disorder associated with alcohol cessation.

(54) The use of the above (46) or (47), wherein the alcohol-inducedsleep disorder is insomnia associated with alcohol cessation.

(55) The use of any one of the above (43)-(45), wherein the sleepdisorder is an insomnia condition, a hypersomnia condition, a circadianrhythm sleep-wake disorder, or any combination thereof.

(56) The use of the above (55), wherein the sleep disorder is aninsomnia condition which is insomnia, child insomnia,middle-of-the-night insomnia, short sleeper disorder, or any combinationthereof.

(57) The use of the above (55) or (56), wherein the insomnia conditionis insomnia.

(58) The use of the above (55) or (56), wherein the insomnia conditionis child insomnia.

(59) The use of the above (55) or (56), wherein the insomnia conditionis middle-of-the-night insomnia.

(60) The use of the above (55) or (56), wherein the insomnia conditionis short sleeper disorder.

(61) The use of the above (55), wherein the sleep disorder is ahypersomnia condition which is insufficient sleep syndrome.

(62) The use of the above (55), wherein the sleep disorder is acircadian rhythm sleep-wake disorder which is delayed sleep-wake phase,advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hoursleep-wake rhythm, shift work syndrome, jet lag, or any combinationthereof.

(63) The use of the above (55) or (62), wherein the circadian rhythmsleep-wake disorder is delayed sleep-wake phase.

(64) The use of the above (55) or (62), wherein the circadian rhythmsleep-wake disorder is advanced sleep-wake phase.

(65) The use of the above (55) or (62), wherein the circadian rhythmsleep-wake disorder is irregular sleep-wake rhythm.

(66) The use of the above (55) or (62), wherein the circadian rhythmsleep-wake disorder is non-24-hour sleep-wake rhythm.

(67) The use of the above (55) or (62), wherein the circadian rhythmsleep-wake disorder is shift work syndrome.

(68) The use of the above (55) or (62), wherein the circadian rhythmsleep-wake disorder is jet lag.

(69) A pharmaceutical composition for treating or preventing a sleepdisorder, comprising the compound or a pharmaceutically acceptable saltthereof as defined in any one of the above (1)-(4), (6), (7), and(38)-(42) or the compound as defined in the above (5).

(70) The pharmaceutical composition of the above (69), wherein the sleepdisorder is an insomnia condition, a hypersomnia condition, a circadianrhythm sleep-wake disorder, an alcohol-induced sleep disorder, or anycombination thereof.

(71) The pharmaceutical composition of the above (70), wherein thealcohol-induced sleep disorder is insomnia-type alcohol-induced sleepdisorder, daytime sleepiness type alcohol-induced sleep disorder,parasomnia type alcohol-induced sleep disorder, mixed typealcohol-induced sleep disorder, insomnia in alcohol use disorder, asleep disorder associated with alcohol cessation, insomnia associatedwith alcohol cessation, or any combination thereof.

(72) The pharmaceutical composition of the above (71), wherein thealcohol-induced sleep disorder is treated.

(73) The pharmaceutical composition of the above (71), wherein thealcohol-induced sleep disorder is prevented.

(74) The pharmaceutical composition of the above (69) or (70), whereinthe sleep disorder is an insomnia condition, a hypersomnia condition, acircadian rhythm sleep-wake disorder, or any combination thereof.

(75) The pharmaceutical composition of the above (69) or (74), whereinthe insomnia condition is insomnia, child insomnia, middle-of-the-nightinsomnia, short sleeper disorder, or any combination thereof.

(76) The pharmaceutical composition of the above (75), wherein theinsomnia condition is treated.

(77) The pharmaceutical composition of the above (75), wherein theinsomnia condition is prevented.

(78) The pharmaceutical composition of the above (69) or (74), whereinthe hypersomnia condition is insufficient sleep syndrome.

(79) The pharmaceutical composition of the above (78), wherein thehypersomnia condition is treated.

(80) The pharmaceutical composition of the above (78), wherein thehypersomnia condition is prevented.

(81) The pharmaceutical composition of the above (69) or (74), whereinthe circadian rhythm sleep-wake disorder is delayed sleep-wake phase,advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hoursleep-wake rhythm, shift work syndrome, jet lag, or any combinationthereof.

(82) The pharmaceutical composition of the above (81), wherein thecircadian rhythm sleep-wake disorder is treated.

(83) The pharmaceutical composition of the above (81), wherein thecircadian rhythm sleep-wake disorder is prevented.

(84) The pharmaceutical composition of any one of the above (69)-(83),wherein the composition further comprises a pharmaceutically acceptablecarrier or excipient.

In one embodiment, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, demonstrates suitableaqueous solubility at a pH of about 6.8. In other embodiments, theaqueous solubility at a pH of about 6.8 of a compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof, is at least about 20 μM, at least about 25 μM, at least about30 μM, at least about 32 μM, at least about 33 μM, at least about 34 μM,at least about 35 μM, at least about 36 μM, at least about 37 μM, atleast about 40 μM, at least about 45 μM, at least about 50 μM, at leastabout 55 μM, at least about 60 μM, at least about 70 μM, or greater thanabout 50 μM. In other embodiments, the aqueous solubility at a pH ofabout 6.8 of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, is from about 20 μM togreater than about 50 μM, from about 25 μM to greater than about 50 μM,from about 30 μM to greater than about 50 μM, from about 32 μM togreater than about 50 μM, from about 33 μM to greater than about 50 μM,from about 34 μM to greater than about 50 μM, from about 35 μM togreater than about 50 μM, from about 36 μM to greater than about 50 μM,from about 37 μM to greater than about 50 μM, from about 40 μM togreater than about 50 μM, from about 20 μM to about 70 μM, from about 25μM to about 70 μM, from about 30 μM to about 70 μM, from about 32 μM toabout 70 μM, from about 33 μM to about 70 μM, from about 34 μM to about70 μM, from about 35 μM to about 70 μM, from about 36 μM to about 70 μM,from about 37 μM to about 70 μM, or from about 40 μM to about 70 μM. Itshould be noted that a compound that is insoluble in aqueous solutionhas an aqueous solubility <0.1 μM. The aqueous solubility values, at apH of about 6.8, in this paragraph can be determined by the procedureprovided in Example 7 herein.

In one embodiment, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, demonstrates suitablerat metabolic stability. In other embodiments, the rat metabolicstability of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, is at least about 60%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, at least about 91%, at least about 92%,at least about 93%, at least about 94%, or at least about 95%. The ratmetabolic stability values in this paragraph can be determined by the invitro procedure provided in Example 8 herein.

In one embodiment, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, demonstrates suitablehuman metabolic stability. In other embodiments, the human metabolicstability of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, is at least about 35%,at least about 40%, at least about 45%, at least about 50%, at leastabout 55%, at least about 60%, at least about 70%, at least about 75%,at least about 80%, at least about 85%, at least about 90%, at leastabout 91%, at least about 92%, at least about 93%, at least about 94%,or at least about 95%. The human metabolic stability values in thisparagraph can be determined by the in vitro procedure provided inExample 8 herein.

In one embodiment, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, demonstrates suitablebioavailability in an animal. In other embodiments, the averagebioavailability of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, is at least about 20%,at least about 25%, at least about 30%, at least about 35%, at leastabout 40%, at least about 45%, at least about 50%, at least about 55%,or at least about 60%. In other embodiments, the average bioavailabilityof a compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, is from about 20% to about 60%, from about25% to about 60%, from about 30% to about 55%, from about 35% to about50%, from about 35% to about 50%, from about 40% to about 50%, or fromabout 40% to about 45%. The average bioavailability values in thisparagraph can be determined by the procedure provided in Example 9herein.

In one embodiment, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, demonstrates asuitable fraction unbound. In other embodiments, the fraction unbound ofa compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, is at least about 25%, at least about 30%,at least about 35%, at least about 40%, at least about 45%, at leastabout 50%, at least about 55%, at least about 60%, at least about 62%,at least about 63%, at least about 64%, at least about 65%, at leastabout 66%, at least about 67%, at least about 68%, at least about 69%,or at least about 70%. In other embodiments, the fraction unbound of acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, is from about 25% to about 90%, from about25% to about 80%, from about 30% to about 80%, from about 35% to about80%, from about 40% to about 80%, from about 45% to about 80%, fromabout 50% to about 80%, from about 55% to about 80%, from about 60% toabout 80%, from about 60% to about 75%, from about 62% to about 75%,from about 62% to about 73%, from about 63% to about 72%, or from about64% to about 72%. The fraction unbound values in this paragraph can bedetermined by the in vitro procedure provided in Example 10 herein.

In one embodiment, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, demonstrates minimalpenetration across the central nervous system (“CNS”) blood-brainbarrier in an animal Such minimally-penetrating compounds are referredto as “peripherally restricted”. In connection with this tissueselectivity, it is useful to define as K_(p) as the ratio of thequantity of a compound that penetrates across an animal's blood-brainbarrier into the CNS (e.g., as determined from the quantity of thecompound in a whole brain homogenate) to the quantity of the compoundcirculating in the animal's plasma.

In other embodiments, the CNS:plasma ratio (or K_(p)) of a peripherallyrestricted compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, is about 1:3, about1:4, about 1:5, about 1:10, about 1:15, about 1:17, about 1:20, about1:23, about 1:24, about 1:25, about 1:26, about 1:27, about 1:30, about1:35, about 1:37, about 1:38, about 1:40, about 1:42, about 1:45, about1:50, about 1:60, about 1:100, about 1:250, about 1:500, about 1:1,000,about 1:5,000, or about 1:10,000. In other embodiments, the CNS:plasmaratio of a peripherally restricted compound of formula (1), (1A), (1B),or (1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof, is fromabout 1:3 to about 1:250, from about 1:4 to about 1:250, from about 1:5to about 1:100, from about 1:10 to about 1:50, from about 1:15 to about1:60, from about 1:20 to about 1:50, from about 1:23 to about 1:45, orfrom about 1:25 to about 1:40. The CNS:plasma ratio values in thisparagraph can be determined by the in vivo procedure provided in Example11 herein.

A compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, can be tested for the ability to penetrateinto the CNS using in vitro and in vivo methods known in the art suchas, e.g., the in vivo method disclosed in Example 11 herein. Certaincompounds of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or compounds of formula (1D), (1E),or (1F) or a solvate thereof, exhibit a reduced propensity toblood-brain barrier penetration as measured by the Madin Darby caninekidney (“MDCK”) cell-line transport assay disclosed in, e.g., Wang etal. (“Evaluation of the MDR-MDCK cell line as a permeability screen forthe blood-brain barrier,” Int. J. Pharm. 288(2):349-359 (2005)).

In one embodiment, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, demonstrates suitablerat protein binding. In other embodiments, the rat protein binding of acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, is at least about 10%, at least about 15%,at least about 20%, at least about 25%, at least about 30%, at leastabout 35%, at least about 40%, at least about 42%, at least about 44%,at least about 46%, at least about 47%, at least about 48%, at leastabout 49%, at least about 50%, at least about 51%, at least about 52%,or at least about 55%. In other embodiments, the rat protein binding ofa compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, is from about 15% to about 75%, from about20% to about 75%, from about 30% to about 75%, from about 35% to about70%, from about 35% to about 65%, from about 35% to about 60%, fromabout 40% to about 60%, from about 42% to about 59%, from about 44% toabout 57%, from about 46% to about 55%, from about 48% to about 53%, orfrom about 49% to about 52%. The rat protein binding values in thisparagraph can be determined by the in vitro procedure provided inExample 12 herein.

5.1 Stages of Sleep

Mammalian sleep can be divided into two distinct types: non-rapid eyemovement (“NREM”) sleep and rapid eye movement (“REM”) sleep. NREM sleepis further divided into a series of distinct stages generally referredto as Stages N1 through N3. Stage N1 or light sleep is generally viewedas the transition between being awake and being asleep. Stage N1 ischaracterized by a slowing in breathing and heart rate during thetransition from being awake to being asleep. Stage N2 or true sleeptypically follows Stage N1, is considered as baseline sleep, andoccupies roughly half of the time asleep. Stage N2 is characterized bymuscle relaxation, reduced or limited eye movement, and reduced orlimited body movement. Stage N3 is referred to as “delta” or “slow wave”sleep and is generally recognized to be the deepest and most restorativestage of sleep. Stage N3 is characterized by additional slowing ofbreathing and heart rate. Arousal from Stage N3 can be difficult. Forthe purposes of FIGS. 5C-18C, for the 24 hour period encompassed in aparticular figure the percentage of NREM sleep is calculated as 100×(thenumber of hours of NREM sleep in that 24 hour period)/24.

REM sleep, sometimes referred to as dream sleep, consists of an activestage of sleep with characteristic rapid eye movements as the sleeperhas vivid dreams. REM sleep is recognized as a separate sleep typebecause of its more distinct reduction of muscle tone and no bodymovement; however, breathing and heart rate may increase and becomeirregular during REM sleep. For the purposes of FIGS. 5B-18B, for the 24hour period encompassed in a particular figure the percentage of REMsleep is calculated as 100×(the number of hours of REM sleep in that 24hour period)/24.

Each of these sleep types and stages has a telltale EEG pattern and,over a single night of sleep a sleeper will generally cycle throughthese types and stages a number of times. Each 30 second unit of timeover the course of sleep can be referred to as an “epoch” and, based onthe EEG pattern obtained during sleep, a sleep technologist is able toassign a sleep type and/or stage (or an awake designation) to each suchepoch.

5.2 Sleep Disorders

As noted above, under one classification scheme six broad categories ofsleep disorders have been identified: (i) insomnia, (ii) hypersomnia,(iii) parasomnia, (iv) circadian rhythm sleep-wake disorders, (v)sleep-related breathing disorders, and (vi) sleep movement disorders.Multiple subcategories are recognized within each of these broadcategories. Each category and subcategory is defined as a “Condition”.For example, the Condition insomnia involves the inability to fallasleep or to stay asleep. The Condition insomnia includes insomnia(“adult” insomnia), also sometimes known as sleep-onset insomnia,insomnia disorder, or “primary insomnia” to distinguish it from theCondition insomnia, i.e., the inability of an adult to fall asleep atthe desired beginning of sleep; child insomnia, i.e., the inability of achild to stay asleep or to fall asleep, e.g., because of a refusal to goto bed or reluctance to allow a parent to leave the bedside;middle-of-the-night insomnia (or “MOTN insomnia”), also known as sleepmaintenance insomnia, middle insomnia, middle-of-the-night awakening (or“MOTN awakening”), and/or nocturnal awakening, i.e., waking up in themiddle of the night followed by difficulty in resuming sleep; and shortsleeper disorder i.e., adults who feel refreshed and alert aftersleeping less than six hours per night. Adult insomnia is also known asearly insomnia and can be assessed through the prolongation of LPS.Adult insomnia/early insomnia/insomnia disorder/primary insomnia is notbrought about by a disease or the use/abuse of a substance. MOTNinsomnia can be assessed through the prolongation of WASO and/orincreased number of awakenings (“NAW”).

As also noted above, under another classification scheme ten broadprimary categories of sleep disorders have been identified: (1) insomniadisorder, (2) hypersomnolence disorder, (3) narcolepsy, (4)breathing-related sleep disorders, (5) circadian rhythm sleep-wakedisorders, (6) non-REM sleep arousal disorders, (7) nightmare disorder,(8) REM sleep behavior disorder, (9) restless leg syndrome, and (10)substance/medication-induced sleep disorder. Multiple subcategories arerecognized within each of these broad categories. Each category andsubcategory is also defined as a “Condition”. For example, the Conditionsubstance/medication-induced sleep disorder involves a prominent sleepdisturbance that is sufficiently severe to warrant independent clinicalattention and that is judged to be primarily associated with thepharmacological effects of a substance, e.g., alcohol (i.e., ethylalcohol). The Condition substance/medication-induced sleep disorderincludes insomnia-type substance/medication-induced sleep disorder,daytime sleepiness type substance/medication-induced sleep disorder,parasomnia type substance/medication-induced sleep disorder, and mixedtype substance/medication-induced sleep disorder. The mixed type relatesto more than one type of these sleep disturbance-related symptoms beingpresent but none predominating Thus, a Condition that can be treatedand/or prevented includes alcohol-induced sleep disorder and any/all ofits subcategories: insomnia-type alcohol-induced sleep disorder, daytimesleepiness type alcohol-induced sleep disorder, parasomnia typealcohol-induced sleep disorder, and mixed type alcohol-induced sleepdisorder. In alcohol-induced sleep disorder, there is evidence ofintoxication or withdrawal from the alcohol and the sleep disorder isassociated with intoxication, discontinuation, or withdrawal therefrom.Other allied Conditions that can be treated and/or prevented includeinsomnia in alcohol use disorder, sleep disturbances associated withalcohol cessation, and/or insomnia associated with alcohol cessation.

The Condition hypersomnia, also sometimes known as hypersomnolencedisorder, causes excessive sleepiness. People with hypersomnia may lackenergy, have difficulty thinking clearly, and/or fall asleep atinconvenient or even dangerous times, such as while working or driving.The Condition hypersomnia includes narcolepsy, i.e., the feeling ofoverwhelming tiredness with a potential for sudden uncontrollable sleepattacks, which is classified as a primary condition under some schemes;idiopathic hypersomnia, i.e., lifelong daily periods of an irrepressibleurge to sleep, e.g., for 12 to 14 hours over a 24 hour period;Kleine-Levin syndrome, i.e., recurrent (more than once a year) two dayto five week periods involving excessive sleepiness; insufficient sleepsyndrome, i.e., the regular failure to get enough sleep at nightresulting in sleep deprivation; and long sleeper disorder i.e., regularsleep of normal and good quality, but much greater in length than otherssimilarly situated (e.g., of similar age).

The Condition parasomnia involves unwanted experiences or events thatoccur during sleep or while falling asleep, or while waking up. Thebehaviors may be complex and appear purposeful to others, but thesleeper remains asleep during the event and often has no memory that ithas occurred. The Condition parasomnia includes confusional arousal,i.e., acting in a strange confused way upon or just after awakening;sleepwalking, also sometimes known as a non-REM sleep arousal disorder,i.e., arising from bed and walking while still asleep and, if awakening,not knowing how he or she arrived at the site of awakening, which isclassified as a primary condition under some schemes; sleep terror, alsosometimes known as a non-REM sleep arousal disorder, i.e., waking withintense fear but with little or no memory of a terrifying dream, whichis classified as a primary condition under some schemes; sleep eatingdisorder, i.e., binge eating while only partially awake with little orno memory of the binge; REM sleep behavior disorder, i.e., acting outvivid dreams, e.g., by punching or flailing, while asleep, which isclassified as a primary condition under some schemes; sleep paralysis,i.e., being unable to move the body upon falling asleep or awakening;nightmare, also sometimes known as nightmare disorder, i.e., dreamsarousing intense feelings of fear, horror and/or distress that may causefear of going to sleep or difficulty in falling back asleep, which isclassified as a primary condition under some schemes; bedwetting, i.e.,failure to awaken to eliminate when the bladder is full; sleephallucination, i.e., imagined events that seem very real, often visualbut may also involve other senses; exploding head syndrome, i.e.,hearing a loud imaginary noise just before falling asleep or awakening;and sleep talking, i.e., often loud, sometimes nonsensical speakingwhile asleep.

The Condition circadian rhythm sleep-wake disorder involves sleep timesthat are out of alignment with the normal day/night cycle and/or the 24hour clock. The Condition circadian rhythm sleep-wake disorder includesdelayed sleep-wake phase, i.e., where a sleep pattern is delayed by twoor more hours so sleep occurs later at night and awakening later in themorning; advanced sleep-wake phase, i.e., falling asleep several hoursbefore normal bedtime and, correspondingly, waking up earlier; irregularsleep-wake rhythm, i.e., sleep patterns being so disorganized that thereis no clear sleeping-waking schedule; non-24-hour sleep-wake rhythm,i.e., the sleeper's sleep time shifts later each day so that it maybecome, over time, misaligned with the desired sleep pattern; shift worksyndrome, i.e., having a work schedule with periodically variablestarting and ending times such that sleep quality is poor and thedevelopment of consistent feelings of fatigue or exhaustion; and jetlag, i.e., difficulty in adjusting the sleep schedule after travelingacross multiple time zones.

The Condition sleep-related breathing disorder, also sometimes known asbreathing-related sleep disorder, involves difficulty in breathingduring sleep. The Condition sleep-related breathing disorder includesobstructive sleep apnea, i.e., the stoppage of breathing during sleepbecause of a blockage in the airways; snoring, i.e., making loud noisesduring sleep caused by vibration of tissues in the back of the throat;central sleep apnea, i.e., the decrease or stoppage of breathing duringsleep caused by a brain or heart problem and not by an obstruction inthe airways; child sleep apnea, i.e., the stoppage of breathing duringsleep in children because of the large size of the tonsils and adenoidswhen compared to the throat; infant sleep apnea, i.e., the stoppage ofbreathing during sleep in infants because of a developmental problemresulting from an immature brainstem or other medical condition; andsleep-related groaning, i.e., making a prolonged noise resemblinggroaning caused by exhaling during sleep.

The Condition sleep movement disorder involves movement during sleep orprior to sleep. These disorders can cause difficulty in falling asleep,remaining asleep, and/or obtaining restful sleep. The Condition sleepmovement disorder includes restless leg syndrome, i.e., burning oritching inside of the legs when lying down that makes gettingcomfortable and falling asleep difficult, which is classified as aprimary condition under some schemes; periodic limb movement syndrome,i.e., a series of uncontrollable, repetitive muscle movements, typicallyof the lower legs, that disrupt sleep; sleep leg cramp, i.e., sudden andintense feelings of pain in the foot or leg caused by muscle contractionand tightening during sleep; and sleep rhythmic movement syndrome, i.e.,repeated body movements such as rocking, head banging or head rollingwhile asleep or falling asleep.

5.3 ORL-1 Expression

Examples of tissue comprising cells capable of expressing the ORL-1receptor include but are not limited to brain, spinal cord, vasdeferens, and gastrointestinal tract tissue. Methods for assaying cellsthat express the ORL-1 receptor are known in the art; for example, seeShimohigashi et al., “Sensitivity of Opioid Receptor-like Receptor ORL1for Chemical Modification on Nociceptin, a Naturally OccurringNociceptive Peptide,” J. Biol. Chem. 271(39):23642-23645 (1996); Naritaet al., “Identification of the G-protein Coupled ORL1 Receptor in theMouse Spinal Cord by [³⁵S]-GTPγS Binding and Immunohistochemistry,”Brit. J. Pharmacol. 128:1300-1306 (1999); Milligan, “Principles:Extending the Utility of [³⁵S]GTPγS Binding Assays,” TIPS 24(2):87-90(2003); and Lazareno, “Measurement of Agonist-stimulated [³⁵S]GTPγSBinding to Cell Membranes,” Methods in Molecular Biology 106:231-245(1999).

It is known that mammalian species display differences in ORL-1 receptorexpression. For example, in the nucleus accumbens and caudate putamen,rodents have relatively low levels of ORL-1 receptor expression (Florinet al., “Autoradiographic localization of [³H]nociceptin binding sitesin the rat brain,” Brain Res. 880:11-16 (2000); Neal et al., “Opioidreceptor-like (ORL1) receptor distribution in the rat central nervoussystem: Comparison of ORL1 receptor mRNA expression with¹²⁵I-[14Tyr]-orphanin FQ binding,” J. Compar. Neurol. 412(4):563-605(1999)). In contrast, monkeys and humans have moderate to high levels ofexpression in these regions (Bridge et al., “Autoradiographiclocalization of ¹²⁵I[¹⁴Tyr] nociceptin/orphanin FQ binding sites inMacaque primate CNS,” Neurosci. 118:513-523 (2003); Berthele et al.,“[³H]-Nociceptin ligand-binding and nociception opioid receptor mRNAexpression in the human brain,” Neurosci. 121:629-640 (2003)). Inanother example, rodents have relatively low levels of ORL-1 receptorexpression in the cerebellar cortex, while monkeys and humans havemoderate to high levels of expression in these regions. Moreover,rodents have relatively low levels of expression of ORL-1 in lamina Iand II of the prefrontal cortex (“PFC”), while humans have moderate tohigh levels of expression in lamina I and II of the PFC. Thus,references such as those above disclose notable supra-spinal speciesdifferences in ORL-1 expression and protein localization, which may beof physiological consequence.

It is well known that one of the nuclei of the brain's hypothalamus, theSCN, is the master controller of the sleep cycle in humans (Richardson,“The Human Circadian System in Normal and Disordered Sleep,” J. Clin.Psychiatry 66(Suppl. 9):3-9 (2005)). The SCN is made up of a network ofnerve cells that fire together with the circadian rhythm. When injectedunilaterally into the SCN of Syrian hamsters, nociceptin, the endogenousligand of the ORL-1 receptor, modulated the activity of SCN neurons andthe response of the circadian clock to light (Allen et al., J. Neurosci.19(6):2152-2160 (1999)). An ORL-1 agonist (W-212393) induced a phaseadvance in the circadian body temperature rhythm of rats by suppressionof rhythmic firing of SCN neurons (Teshima et al., Br. J. Pharmacol.146(1):33-40 (2005)). These references demonstrate that modulating theORL-1 receptor in the brain can influence circadian-related processessuch as, e.g., sleep.

It is also recognized that portions of the hypothalamus are onlypartially protected by the blood-brain-barrier (De la Torre, J. Neurol.Sci. 12(1):77-93 (1971)). While not wishing to be bound by theory, it ispossible that a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof is able to gain accessto the SCN or other related nuclei in humans, stimulate ORL-1 receptorstherein, and produce fatigue and/or somnolence via modulation of therhythmic firing pattern of the SCN neurons or other related nuclei.

According to the present disclosure, some compounds of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or of formula (1D), (1E), or (1F) or a solvate thereof arepartial agonists at the human ORL-1 receptor. In another embodiment, acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof is a partial agonist at the human ORL-1receptor and an antagonist at a human mu, kappa, and/or delta opioidreceptor. In another embodiment, a compound of formula (1), (1A), (1B),or (1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof is apartial agonist at the human ORL-1 receptor and an antagonist at thehuman μ opioid receptor.

5.4 Definitions

As used in connection with the compounds of formula (1), (1A), (1B),(1C) and their pharmaceutically acceptable salts and/or solvates, andthe compounds of formula (1D), (1E), (1F) and their solvates, and theirmethods of use, the terms used herein have the following meanings.

The term “Time in Bed” (“TIB”) refers to the duration of time, e.g., inminutes, of an entire intended sleep episode from its beginning to itsend. TIB is often of a fixed duration, e.g., 480 minutes.

The term “Total Sleep Time” (“TST”) refers to the sum of all timeepochs, e.g., in minutes, spent in either NREM (including all of StagesN1 through N3) or REM sleep.

The term “Sleep Efficiency” (“SE”) is measured by polysomnography ininsomnia subjects and refers to the fraction of the TIB that is spentasleep in REM and NREM sleep and is calculated as the following ratio:TST/TIB. Alternately, SE can be expressed as a percentage by multiplyingthis ratio by 100. SE is a measure of sleep maintenance throughout thenight, thus, assessment of SE also includes, inter alia, assessment ofprolonged LPS and/or assessment of prolonged WASO.

The term “Latency to Persistent Sleep” (“LPS”) refers to the time, e.g.,in minutes, from the beginning of the TIB until the start of a period ofleast 10 uninterrupted minutes of sleep epochs—in any sleep stage. LPSis a measure of the “speed” of going to sleep.

The term “Total Wake Time” (“TWT”) refers, for the TIB, to the totaltime, e.g., in minutes, of epochs spent awake, i.e., not in any sleepstage.

The term “Wake During Sleep” (“WDS”) refers to the total time, e.g., inminutes, of epochs spent awake occurring after the onset of persistentsleep (defined as at least 10 consecutive minutes of sleep epochs of anysleep stage) and before the onset of the final epoch of sleep (of anysleep stage) during the TIB.

The term “Wake After Sleep” (“WAS”) refers to the duration, e.g., inminutes, of time spent awake after the conclusion of final sleep epoch(of any sleep stage) until the end of the TIB.

The term “Wake After Sleep Onset” (“WASO”) refers to the sum of WDS andWAS. WASO is another measure of sleep maintenance throughout the night.

The term “Number of Awakenings” (“NAW”) refers to the number of timesafter onset of persistent sleep in which an awakening for a period ofgreater than 30 seconds occurs.

The term “REM latency” refers to the time, e.g., in minutes, from thebeginning of the TIB until the beginning of the first epoch of REMsleep.

For the purposes of FIGS. 5A-18A, for the 24 hour period encompassed ina particular figure the percentage of “wakefulness” is calculated as100×(the number of hours spent awake (i.e., not in either REM sleep orin NREM sleep) in that 24 hour period)/24.

The term “animal” includes, but is not limited to, a human or anon-human mammal, such as a companion animal or livestock, e.g., a cow,monkey, baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail,cat, dog, mouse, rat, rabbit or guinea pig. In one embodiment, an animalis a human.

The term “pharmaceutically acceptable salt”, as used herein, is anypharmaceutically acceptable salt that can be prepared from a compound offormula (1), (1A), (1B), or (1C) or is the pharmaceutically acceptablesalt shown herein as formula (1D), (1E), or (1F) including a salt formedfrom an acid and a basic functional group, such as a nitrogen group, ofa compound of formula (1), (1A), (1B), or (1C). Illustrative saltsinclude, but are not limited, to sulfate, citrate, acetate,trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a compound of formula (1), (1A), (1B), or (1C) having anacidic functional group, such as a carboxylic acid functional group, anda pharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, cesium, and lithium; hydroxides of alkaline earthmetal such as calcium and magnesium; hydroxides of other metals, such asaluminum and zinc; ammonia and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines, such asN-methyl-N-ethylamine, diethylamine, triethylamine, tributyl amine,(tert-butylamino)methanol, and tris-(hydroxymethyl)amine;dicyclohexylamine; pyridine; picoline; mono-, bis-, ortris-(2-hydroxy-(C₁-C₃)alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, andN,N-di-[(C₁-C₃)alkyl]-N-(hydroxy-(C₁-C₃)alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine; N-methyl-D-glucamine; an aminoacid, such as arginine and lysine; an amino acid derivative, such ascholine (i.e., 2-hydroxy-N,N,N-trimethylethan-1-aminium), a derivativeof the amino acid serine; and the like. In one embodiment, thepharmaceutically acceptable salt is a hydrochloride salt, a sulfatesalt, a sodium salt, a potassium salt, a benzene sulfonic acid salt, apara-toluenesulfonic acid salt, or a fumaric acid salt. In anotherembodiment, the pharmaceutically acceptable salt is a hydrochloride saltor a sulfate salt. In another embodiment, the pharmaceuticallyacceptable salt is a hydrochloride salt. In another embodiment, thepharmaceutically acceptable salt is a sulfate salt. In anotherembodiment, the pharmaceutically acceptable salt is a sodium salt. Inanother embodiment, the pharmaceutically acceptable salt is a potassiumsalt. In another embodiment, the pharmaceutically acceptable salt is afumaric acid salt. In another embodiment, the pharmaceuticallyacceptable salt is a para-toluenesulfonic acid salt. In anotherembodiment, the pharmaceutically acceptable salt is a choline salt.

In another embodiment, the pharmaceutically acceptablepara-toluenesulfonic acid salt contains one equivalent of a compound offormula (1), (1A), (1B), or (1C) and about 1.0 equivalent ofpara-toluenesulfonic acid, e.g., from about 0.8 to about 1.2 equivalentsof para-toluenesulfonic acid in one embodiment, from about 0.9 to about1.1 equivalents of para-toluenesulfonic acid in another embodiment, fromabout 0.93 to about 1.07 equivalents of para-toluenesulfonic acid inanother embodiment, from about 0.95 to about 1.05 equivalents ofpara-toluenesulfonic acid in another embodiment, from about 0.98 toabout 1.02 equivalents of para-toluenesulfonic acid in anotherembodiment, or from about 0.99 to about 1.01 equivalents ofpara-toluenesulfonic acid in another embodiment. In another embodiment,the pharmaceutically acceptable para-toluenesulfonic acid salt containsabout one equivalent of a compound of formula (1), (1A), (1B), or (1C)and about one equivalent of para-toluenesulfonic acid, i.e., is amono-tosylate salt. In another embodiment, the pharmaceuticallyacceptable para-toluenesulfonic acid salt contains one equivalent of acompound of formula (1), (1A), (1B), or (1C) and about one equivalent ofpara-toluenesulfonic acid. In another embodiment, the pharmaceuticallyacceptable para-toluenesulfonic acid salt contains one equivalent of acompound of formula (1), (1A), (1B), or (1C) and one equivalent ofpara-toluenesulfonic acid. The mono-tosylate salt of the compound offormula (1C), i.e., the compound of formula (1D), is as follows:

In another embodiment, the pharmaceutically acceptable hydrochloridesalt contains one equivalent of a compound of formula (1), (1A), (1B),or (1C) and about 1.0 equivalent of hydrochloric acid, e.g., from about0.8 to about 1.2 equivalents of hydrochloric acid in one embodiment,from about 0.9 to about 1.1 equivalents of hydrochloric acid in anotherembodiment, from about 0.93 to about 1.07 equivalents of hydrochloricacid in another embodiment, from about 0.95 to about 1.05 equivalents ofhydrochloric acid in another embodiment, from about 0.98 to about 1.02equivalents of hydrochloric acid in another embodiment, or from about0.99 to about 1.01 equivalents of hydrochloric acid in anotherembodiment. In another embodiment, the pharmaceutically acceptablehydrochloride salt contains about one equivalent of a compound offormula (1), (1A), (1B), or (1C) and about one equivalent ofhydrochloric acid, i.e., is a mono-hydrochloride salt. In anotherembodiment, the pharmaceutically acceptable hydrochloride salt containsone equivalent of a compound of formula (1), (1A), (1B), or (1C) andabout one equivalent of hydrochloric acid. In another embodiment, thepharmaceutically acceptable hydrochloride salt contains one equivalentof a compound of formula (1), (1A), (1B), or (1C) and one equivalent ofhydrochloric acid. The mono-hydrochloride salt of the compound offormula (1C) is the compound of formula (1E). One skilled in the artwill recognize that acid addition salts of a compound of formula (1),(1A), (1B), or (1C) for use in the methods of the disclosure can beprepared by reaction of each compound with the appropriate acid by avariety of known methods.

In another embodiment, the pharmaceutically acceptable choline saltcontains one equivalent of a compound of formula (1), (1A), (1B), or(1C) and about 1.0 equivalent of choline, e.g., from about 0.8 to about1.2 equivalents of choline in one embodiment, from about 0.9 to about1.1 equivalents of choline in another embodiment, from about 0.93 toabout 1.07 equivalents of choline in another embodiment, from about 0.95to about 1.05 equivalents of choline in another embodiment, from about0.98 to about 1.02 equivalents of choline in another embodiment, or fromabout 0.99 to about 1.01 equivalents of choline in another embodiment.In another embodiment, the pharmaceutically acceptable choline saltcontains about one equivalent of a compound of formula (1), (1A), (1B),or (1C) and about one equivalent of choline, i.e., is a mono-cholinesalt. In another embodiment, the pharmaceutically acceptable cholinesalt contains one equivalent of a compound of formula (1), (1A), (1B),or (1C) and about one equivalent of choline. In another embodiment, thepharmaceutically acceptable choline salt contains one equivalent of acompound of formula (1), (1A), (1B), or (1C) and one equivalent ofcholine. The mono-choline salt of the compound of formula (1C) is thecompound of formula (1F). One skilled in the art will recognize thatbase addition salts of a compound of formula (1), (1A), (1B), or (1C)for use in the methods of the disclosure can be prepared by reaction ofeach compound with the appropriate base by a variety of known methods.

The methods of the disclosure provided herein also encompass the use ofany solvate of the compounds of formula (1), (1A), (1B), (1C), (1D),(1E), and (1F). “Solvates” are generally known in the art, and areconsidered herein to be a combination, physical association and/orsolvation of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt thereof, or a compound of formula (1D),(1E), or (1F) with a solvent molecule. This physical association caninvolve varying degrees of ionic and covalent bonding, includinghydrogen bonding. When the solvate is of the stoichiometric type, thereis a fixed ratio of the solvent molecule to the compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt thereof, or acompound of formula (1D), (1E), or (1F), e.g., a di-solvate,mono-solvate or hemi-solvate when the [solvent molecule]: [compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltthereof, or a compound of formula (1D), (1E), or (1F) molecule] molarratio is 2:1, 1:1 or 1:2, respectively. In other embodiments, thesolvate is of the non-stoichiometric type. For example, the compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltthereof, or the compound of formula (1D), (1E), or (1F) crystal cancontain solvent molecules in the structural voids, e.g., channels, ofthe crystal lattice. In certain instances, the solvate can be isolated,for example, when one or more solvent molecules are incorporated intothe crystal lattice of a crystalline solid. Thus, “solvate”, as usedherein, encompasses both solution-phase and isolatable solvates.

A compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt thereof, or a compound of formula (1D), (1E), or (1F) ofthe disclosure can be present as a solvated form with a pharmaceuticallyacceptable solvent, such as water, methanol, ethanol, and the like, andit is intended that the disclosure include both solvated and unsolvatedforms of a compound of formula (1), (1A), (1B), and (1C) or apharmaceutically acceptable salt thereof, and a compound of formula(1D), (1E), and (1F). As “hydrate” relates to a particular subgroup ofsolvates, i.e., where the solvent molecule is water, hydrates areincluded within the solvates of the disclosure. In one embodiment, thecompound of formula (1), (1A), (1B), or (1C) is present as amonohydrate, e.g., as a free base where the water: [compound of formula(1), (1A), (1B), or (1C) or a pharmaceutically acceptable salt thereof,or compound of formula (1D), (1E), or (1F)] molar ratio is about 1:1,e.g., from 0.91:1 to 1.09:1 in one embodiment, from 0.94:1 to 1.06:1 inanother embodiment, from 0.97:1 to 1.03:1 in another embodiment, andfrom 0.985:1 to 1.015:1 in another embodiment, each said embodimenttaking no account of surface water that might be present, if any.

Solvates can be made according to known techniques in view of thepresent disclosure. For example, Caira et al., “Preparation and CrystalCharacterization of a Polymorph, a Monohydrate, and an Ethyl AcetateSolvate of the Antifungal Fluconazole,” J. Pharmaceut. Sci.,93(3):601-611 (2004), describes the preparation of solvates offluconazole with ethyl acetate and with water. Similar preparations ofsolvates, hemi-solvate, hydrates, and the like are described by VanTonder et al., “Preparation and Physicochemical Characterization of 5Niclosamide Solvates and 1 Hemisolvate,” AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and Bingham et al., “Over one hundred solvatesof sulfathiazole,” Chem. Comm., pp. 603-604 (2001). In one embodiment, anon-limiting, process involves dissolving the compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt thereof, orthe compound of formula (1D), (1E), or (1F) in a desired amount of thesolvent (organic, water or mixtures thereof) at temperatures above about20° C. to about 25° C., cooling the solution at a rate sufficient toform crystals, and isolating the crystals by known methods, e.g.,filtration. Analytical techniques, for example, infrared spectroscopy,can be used to show the presence of the solvent in a crystal of thesolvate.

The methods of the disclosure provided herein also encompass the use ofa compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof where one or more hydrogen, carbon or otheratoms is replaced by a radioactive isotope of the hydrogen, carbon orother atoms. Such a “radiolabeled” compound of formula (1), (1A), (1B),or (1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof, each ofwhich is encompassed by the disclosure, is useful as a research and/ordiagnostic tool in metabolism pharmacokinetic studies and in bindingassays. “Radioactive”, as used herein means a compound that comprises atleast one radioactive atom such that the specific radioactivity thereofis above the background level of radioactivity. Examples of radioactiveisotopes that can be incorporated into a compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or a compound of formula (1D), (1E), or (1F) or a solvate thereof of thedisclosure include isotopes of hydrogen, carbon, nitrogen, and oxygen,such as, for example, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, and ¹⁸O. In oneembodiment, a radiolabeled compound of formula (1), (1A), (1B), or (1C)or a pharmaceutically acceptable salt or solvate thereof, or aradiolabeled compound of formula (1D), (1E), or (1F) or a solvatethereof contains 1, 2, 3, 4, or more radioactive isotopes, each of whichis independently selected from hydrogen, carbon, nitrogen, and oxygen.In another embodiment, a radiolabeled compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or a radiolabeled compound of formula (1D), (1E), or (1F) or a solvatethereof contains 1 or 2 radioactive isotopes, each of which isindependently selected from ³H, ¹⁴C, and ¹⁵N. In another embodiment, aradiolabeled compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a radiolabeledcompound of formula (1D), (1E), or (1F) or a solvate thereof contains 1radioactive isotope which is selected from ³H, ¹⁴C, and ¹⁵N. In anotherembodiment, a radiolabeled compound of formula (1), (1A), (1B), or (1C)or a pharmaceutically acceptable salt or solvate thereof, or aradiolabeled compound of formula (1D), (1E), or (1F) or a solvatethereof contains 1 radioactive isotope which is ³H. In anotherembodiment, a radiolabeled compound of formula (1), (1A), (1B), or (1C)or a pharmaceutically acceptable salt or solvate thereof, or aradiolabeled compound of formula (1D), (1E), or (1F) or a solvatethereof contains 1 radioactive isotope which is ¹⁴C. In anotherembodiment, a radiolabeled compound of formula (1), (1A), (1B), or (1C)or a pharmaceutically acceptable salt or solvate thereof, or aradiolabeled compound of formula (1D), (1E), or (1F) or a solvatethereof contains 1 radioactive isotope which is ¹⁵N.

Radiolabeled compounds for use in the methods of the disclosure can beprepared by methods known in the art. For example, a tritiated compoundof formula (1), (1A), (1B), or (1C) or a pharmaceutically acceptablesalt or solvate thereof, or a tritiated compound of formula (1D), (1E),or (1F) or a solvate thereof can be prepared by introducing tritium intothe particular compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or the compound offormula (1D), (1E), or (1F) or a solvate thereof, for example, bycatalytic dehalogenation with tritium. This method can include reactinga suitably halogen-substituted precursor of a compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof with tritium gas in the presence of a suitable catalyst, forexample, Pd/C, in the presence or absence of a base. Other suitablemethods for preparing tritiated compounds can be found in Filer, “ThePreparation and Characterization of Tritiated Neurochemicals,” Isotopesin the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (PartA), Buncel et al., eds., Chapter 6, pp. 155-192 (1987). ¹⁴C-labeledcompounds can be prepared by employing starting materials having a ¹⁴Ccarbon. Compounds containing, e.g., piperazine, isotopically enrichedwith ¹³C and/or ¹⁵N can be prepared as described in, e.g., FIG. 5A andthe associated description, of U.S. Pat. No. 7,355,045 B2.

A compound of formula (1), (1A), or (1B) or a pharmaceuticallyacceptable salt or solvate thereof can contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Unless specifically otherwise indicated, thedisclosure encompasses compounds with all such possible forms as well astheir racemic and resolved forms, and all mixtures thereof. Unlessspecifically otherwise indicated, all “tautomers”, e.g., lactam-lactim,urea-isourea, ketone-enol, amide-imidic acid, enamine-imine,amine-imine, and enamine-enimine tautomers, are intended to beencompassed by the disclosure as well.

As used herein, the terms “stereoisomer”, “stereoisomeric form”, andrelated terms as used herein are general terms for all isomers ofindividual molecules that differ only in the orientation of their atomsin space. It includes enantiomers and isomers of compounds with morethan one chiral center that are not mirror images of one another(“diastereomers”).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposable on its mirror image and hence optically active wherethe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomerswhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule. Opticalisomers of a compound of formula (1), (1A), or (1B) can be obtained byknown techniques such as chiral chromatography or formation ofdiastereomeric salts from an optically active acid or base.

Optical purity can be stated in terms of enantiomeric excess (“% ee”)and/or diastereomeric excess (% de), each which is determined by theappropriate formula below:

${\% \mspace{14mu} {ee}} = {\left\lbrack \frac{{{major}\mspace{14mu} {{enantiomer}({mol})}} - {{minor}\mspace{14mu} {{enantiomer}({mol})}}}{{{major}\mspace{14mu} {{enantiomer}({mol})}} + {{minor}\mspace{14mu} {{enantiomer}({mol})}}} \right\rbrack \times 100\%}$${\% \mspace{14mu} {de}} = {\left\lbrack \frac{{{major}\mspace{14mu} {{diastereomer}({mol})}} - {{minor}\mspace{14mu} {{enantiomer}({mol})}}}{{{major}\mspace{14mu} {{diastereomer}({mol})}} + {{minor}\mspace{14mu} {{enantiomer}({mol})}}} \right\rbrack \times 100{\%.}}$

The term “effective amount”, when used in connection with methods fortreating or preventing a sleep disorder by administering a compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltor solvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, refers to an amount of the compound administered to ananimal that provides a therapeutic effect.

The term “effective amount”, when used in connection with a secondtherapeutic agent means an amount for providing the therapeutic effectof the second therapeutic agent.

The terms “modulate”, “modulating”, and related terms as used hereinwith respect to the ORL-1 receptor mean the mediation of apharmacodynamic response (e.g., insomnia) in an animal from (i)inhibiting or activating the receptor, or (ii) directly or indirectlyaffecting the normal regulation of the receptor activity. Compounds thatmodulate the receptor activity include agonists, partial agonists,antagonists, mixed agonists/antagonists, mixed partialagonists/antagonists and compounds which directly or indirectly affectregulation of the receptor activity.

As used herein, a compound that binds to a receptor and mimics theregulatory effect(s) of an endogenous ligand is defined as an “agonist”.As used herein, a compound that binds to a receptor and is only partlyeffective as an agonist is defined as a “partial agonist”. As usedherein, a compound that binds to a receptor but produces no regulatoryeffect, but rather blocks binding of another agent to the receptor isdefined as an “antagonist”. (See Ross et al., “Pharmacodynamics:Mechanisms of Drug Action and the Relationship Between DrugConcentration and Effect,” in Goodman and Gilman's The PharmacologicalBasis of Therapeutics pp. 31-43 (Goodman et al., eds., 10^(th) Ed.,McGraw-Hill, New York 2001)).

The terms “treatment of”, “treating”, and related terms as used hereininclude the amelioration, reduction, slowing, or cessation of aCondition or a symptom thereof by administration of an effective amountof a compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof. In some embodiments, treating includesinhibiting, for example, decreasing the overall frequency of episodes ofa Condition or a symptom thereof or reducing the severity of a Conditionor a symptom thereof.

The terms “prevention of”, “preventing”, and related terms as usedherein include the avoidance of the onset of a Condition or a symptomthereof by administration of an effective amount of a compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltor solvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof.

A “disorder” includes, but is not limited to, the Conditions definedherein. In one embodiment, a disorder relates to a Condition or symptomof insufficient sleep, or resulting from insufficient sleep, ordifficulty falling asleep or staying asleep.

The amount by weight of the administered “dose”, “dosage”, and relatedterms as used herein refers to the free acid and free base form of acompound of formula (1), (1A), (1B), or (1C), i.e., the no-salt form.For example, a 10.0 mg dose of the no-salt form of the compound offormula (1) means that 10.0 mg is actually administered. However, by wayof example, a 10.0 mg dose of, e.g., the monohydrochloride or the 1:1 bymoles hydrochloric acid salt of the compound of formula (1) (i.e., thecompound of formula (1E)) means that 10.84 mg of said compound isactually administered, which 10.84 mg provides 10.00 mg of the no-saltform of the compound of formula (1) (0.0229 mmoles) and 0.84 mg ofhydrochloric acid (0.0229 mmoles). Also by way of example, a 10.0 mgdose of, e.g., the monosodium salt of the compound of formula (1) meansthat 10.57 mg of said compound is actually administered, which 10.57 mgprovides 10.00 mg of the no-salt form of the compound of formula (1)(0.0229 mmoles) and 0.57 mg of sodium (0.0229 mmoles). Likewise, a 10.00mg dose of, e.g., the mono-tosylate salt (1:1 by molespara-toluenesulfonic acid salt) of the compound of formula (1C), i.e.,the compound of formula (1D), means that 13.93 mg of said compound isactually administered, which 13.93 mg provides 10.00 mg of the no-saltform of the compound of formula (1C) (0.0229 mmoles) and 3.93 mg ofpara-toluenesulfonic acid (0.0229 mmoles).

The term “UI” means urinary incontinence. The term “IBD” meansinflammatory-bowel disease. The term “IBS” means irritable-bowelsyndrome. The term “ALS” means amyotrophic lateral sclerosis.

The term “N/A” as used herein means not applicable.

The term “SD” as used herein means standard deviation.

The term “LSM” as used herein means least-squares mean.

The term “STDE” as used herein means standard error.

In the event of doubt as to the agreement of a depicted chemicalstructure and a chemical name, the depicted chemical structure governs.

It is appreciated that various features of the disclosure which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment unless otherwisespecifically herein excluded. Conversely, various features of thedisclosure which are, for brevity, described in the context of a singleembodiment, can also be provided separately and/or in any suitablesubcombination unless otherwise specifically herein excluded.

5.5 Therapeutic Uses of the Compound of Formula (1), (1A), (1B), (1C),(1D), (1E), and (1F)

In accordance with the disclosure, the compounds of formula (1), (1A),(1B), and (1C) or a pharmaceutically acceptable salt or solvate thereof,and the compounds of formula (1D), (1E), and (1F) or a solvate thereofare administered to an animal in need of treatment or prevention of aCondition.

In one embodiment, an effective amount of a compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof can be used to treat or prevent a sleep disorder treatable orpreventable by modulating the activity of the ORL-1 receptor.

An effective amount of a compound of formula (1), (1A), (1B), or (1C) ora pharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof can be used to treat orprevent a sleep disorder including, but not limited to insomnia, such as“adult” insomnia, child insomnia, middle-of-the-night insomnia, andshort sleeper disorder; hypersomnia, such as insufficient sleepsyndrome; circadian rhythm sleep-wake disorder, such as delayedsleep-wake phase, advanced sleep-wake phase, irregular sleep-wakerhythm, non-24-hour sleep-wake rhythm, shift work syndrome, and jet lag;or any combination thereof. Other sleep disorders that can be treated orprevented by a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof include types ofdyssomnia not already referenced in this paragraph, food allergyinsomnia, alcohol-dependent sleep disorder, and/or alcohol-induced sleepdisorder.

In connection with alcohol-related sleep disorders, DSM-5 also sets outalcohol-induced sleep disorder as a principal diagnosis and subdividesthe sleep disorder into four types: insomnia, daytime sleepiness,parasomnia, and mixed type. It discloses that alcohol-induced sleepdisorder typically occurs as “insomnia type”, that is, sleep disordercharacterized by “difficulty falling asleep or maintaining sleep,frequent nocturnal awakenings, or nonrestorative sleep.” Specifically,Conroy discloses alcohol consumption has a “biphasic” effect on sleepwithin a night. That is, in the earlier portion of the night an alcoholdose can provide an immediate sedative effect with shorter LPS and anincreased duration of Stage N3 sleep. However, in the later portion ofthe night sleep quality deteriorates and there is a greater NAW. Yetanother reference concludes that virtually every type of sleep problemoccurs in alcohol-dependent patients, typically, a long LPS, low SE,short TST, reduced duration of Stage N3 sleep, fragmented sleeppatterns, and severely disrupted sleep architecture (Landolt et al.,“Sleep Abnormalities During Abstinence in Alcohol-Dependent Patients:Aetiology and Management,” CNS Drugs 15(5):413-425 (2001)).

Even alcoholics who have been abstinent, either for short periods oftime (several weeks) or extended periods of time (several years), canexperience persistent sleep abnormalities such as increased LPS,frequent MOTN awakening, and poor sleep quality. In summarizing theresults of multiple studies, Brower concludes that alcoholics who hadbeen abstinent for 2-8 weeks exhibited worse sleep than didnon-alcoholics, that is, TST, SE, and the amount of time spent in StageN3 sleep generally decreased significantly whereas Stage N1 sleep timeusually increased and LPS increased significantly. Moreover, sleepabnormalities can persist for 1-3 years after alcohol consumption ends.For example, Brower concludes that sleep fragmentation, expressed asincreases in sleep-stage changes, brief arousals, and REM sleepdisruptions, can persist for 1-3 years after establishing sobriety.Diminished REM sleep time is understood to be associated with negativecognitive consequences, e.g., poor procedural learning.

Moreover, it is recognized that the consumption of alcohol can damagethe human liver, a vital organ that filters harmful substances from theblood and manufactures various substances, such as hormones, proteins,and enzymes, that the body requires. Alcohol-related liver disease(“ALD”) is caused by excessive consumption of alcohol. Its mildest form,steatosis or fatty liver, is characterized by an excessive accumulationof fat inside liver cells, making liver functioning more difficult. Amore severe form of ALD that can develop from is steatosis is alcoholichepatitis, either chronic or acute. It manifests as the inflammation orswelling of the liver accompanied by the destruction of liver cells andmakes liver functioning even more difficult. The most severe form of ALDthat can develop from excess alcohol consumption is alcoholic cirrhosis.It is characterized by the replacement of normal liver tissue withnonliving scar tissue. Alcoholic cirrhosis can be a life-threateningdisease because of the associated severe impairment of liverfunctioning.

Thus, there remains an unmet need for a safe and effective medication totreat sleep disorders or disturbances, e.g., insomnia, that areassociated with alcohol use disorder, alcohol dependence,alcohol-induced sleep disorder, and/or alcohol cessation. In onedesirable embodiment, such medication would still function effectivelyeven when the liver suffers from alcohol-induced damage in the form ofsteatosis, alcoholic hepatitis, and/or alcoholic cirrhosis.

The disclosure also relates to methods for activating ORL-1 receptorfunction in a cell, comprising contacting a cell capable of expressingthe ORL-1 receptor with an amount of a compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or a compound of formula (1D), (1E), or (1F) or a solvate thereofeffective to activate ORL-1 receptor function in the cell. This methodcan be adapted for use in vitro as part of an assay to select compoundsuseful for treating or preventing a sleep disorder. Alternatively, themethod can be adapted for use in vivo (i.e., in an animal such as ahuman), by contacting a cell in the animal with an effective amount of acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or solvate thereof. In one embodiment, the method is useful fortreating or preventing a sleep disorder in an animal in need of suchtreatment or prevention.

5.6 Therapeutic/Prophylactic Administration and Compositions of theDisclosure

Due to their activity, the compounds of formula (1), (1A), (1B), and(1C) or a pharmaceutically acceptable salt or solvate thereof, and thecompounds of formula (1D), (1E), and (1F) or a solvate thereof areadvantageously useful in human and veterinary medicine. As describedabove, the compounds of formula (1), (1A), (1B), and (1C) or apharmaceutically acceptable salt or solvate thereof, and the compoundsof formula (1D), (1E), and (1F) or a solvate thereof are useful fortreating or preventing a Condition in an animal in need thereof. Inanother embodiment, the compounds of formula (1), (1A), (1B), and (1C)or a pharmaceutically acceptable salt or solvate thereof, and thecompounds of formula (1D), (1E), and (1F) or a solvate thereof areuseful for treating a Condition in an animal in need thereof. In anotherembodiment, the compounds of formula (1), (1A), (1B), and (1C) or apharmaceutically acceptable salt or solvate thereof, and the compoundsof formula (1D), (1E), and (1F) or a solvate thereof are useful forpreventing a Condition in an animal in need thereof. In anotherembodiment, the compounds of formula (1), (1A), (1B), and (1C) or apharmaceutically acceptable salt or solvate thereof, and the compoundsof formula (1D), (1E), and (1F) or a solvate thereof of the disclosurecan be administered to any animal requiring modulation of the opioidand/or ORL-1 receptors.

When administered to an animal, a compound of formula (1), (1A), (1B),or (1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof can beadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous,intranasal, epidural, oral, transmucosal, buccal, gingival, sublingual,intraocular, intracerebral, intravaginal, transdermal (e.g., via apatch), rectal, by inhalation, or topical, particularly to the ears,nose, eyes, or skin. In another embodiment, methods of administrationinclude, but are not limited to, intravenous, oral, or by inhalation. Inanother embodiment, the method of administration is oral. In anotherembodiment, the method of administration is intravenous. In anotherembodiment, the method of administration is by inhalation. The method ofadministration is left to the discretion of the practitioner. In someinstances, administration will result in the release of a compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltor solvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof into the bloodstream. In other instances, administrationwill result in only local release of a compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or a compound of formula (1D), (1E), or (1F) or a solvate thereof.

In certain embodiments, it can be desirable to introduce a compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltor solvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof into the central nervous system or gastrointestinaltract by any suitable route, including intraventricular, intrathecal, orepidural injection, or enema. Intraventricular injection can befacilitated by an intraventricular catheter, for example, attached to areservoir, such as an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof can be formulated as asuppository, with traditional binders and excipients such astriglycerides.

When a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof of the disclosure isincorporated for parenteral administration by injection (e.g.,continuous infusion or bolus injection), the formulation for parenteraladministration can be in the form of a suspension, solution, emulsion inan oily or aqueous vehicle. Such formulations can further comprisepharmaceutically necessary additives such as one or more stabilizingagents, suspending agents, dispersing agents, buffers, and the like. Acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof of the disclosure can also be in the formof a powder for reconstitution as an injectable formulation.

In another embodiment, a compound of formula (1), (1A), (1B), or (1C) ora pharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof can be delivered in avesicle, in particular a liposome (see Langer, “New Methods of DrugDelivery,” Science 249:1527-1533 (1990); and Treat et al., “LiposomeEncapsulated Doxorubicin Preliminary Results of Phase I and Phase IITrials,” pp. 317-327 and 353-365 in Liposomes in the Therapy ofInfectious Disease and Cancer (1989)).

In yet another embodiment, a compound of formula (1), (1A), (1B), or(1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof can bedelivered in a controlled-release system or sustained-release system.Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained-release counterparts. In one embodiment,a controlled- or sustained-release composition comprises a minimalamount of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof to treat or prevent theCondition or a symptom thereof in an extended amount of time. Advantagesof controlled- or sustained-release compositions include extendedactivity of the drug, reduced dosage frequency, and increasedcompliance. In addition, controlled- or sustained-release compositionscan favorably affect the time of onset of action or othercharacteristics, such as blood levels of the compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof, and can thus reduce the occurrence of adverse side effects.

Controlled- or sustained-release compositions can initially release anamount of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof that promptly producesthe desired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or the compound of formula (1D), (1E), or (1F) or a solvate thereof tomaintain this level of therapeutic or prophylactic effect over anextended period of time. To maintain a constant level of the compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltor solvate thereof, or the compound of formula (1D), (1E), or (1F) or asolvate thereof in the body, the compound of formula (1), (1A), (1B), or(1C) or a pharmaceutically acceptable salt or solvate thereof, or thecompound of formula (1D), (1E), or (1F) or a solvate thereof can bereleased from the dosage form at a rate that will replace the amount ofthe compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or the compound of formula (1D),(1E), or (1F) or a solvate thereof being metabolized and excreted fromthe body. Controlled- or sustained-release of an active ingredient canbe stimulated by various conditions, including but not limited to,changes in pH, changes in temperature, concentration or availability ofenzymes, concentration or availability of water, or other physiologicalconditions or compounds. In yet another embodiment, a controlled- orsustained-release system can be placed in proximity of a target of acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, e.g., the spinal column or brain, thusrequiring only a fraction of the systemic dose.

Administration of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof can be bycontrolled-release or sustained-release means or by delivery devicesthat are known to those in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770, 3,916,899,3,536,809, 3,598,123, 4,008,719, 5,674,533, 5,059,595, 5,591,767,5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of whichis incorporated herein by reference. Numerous other controlled-releaseor sustained-release delivery devices that are known to those in the art(see, e.g., Goodson, “Dental Applications,” in Medical Applications ofControlled Release, Vol. 2, Applications and Evaluation, Langer andWise, eds., CRC Press, Chapter 6, pp. 115-138 (1984), hereafter“Goodson”). Other controlled- or sustained-release systems discussed inthe review by Langer, Science 249:1527-1533 (1990) can be used. In oneembodiment, a pump can be used (Langer, Science 249:1527-1533 (1990);Sefton, “Implantable Pumps,” in CRC Crit. Rev. Biomed. Eng.14(3):201-240 (1987); Buchwald et al., “Long-term, ContinuousIntravenous Heparin Administration by an Implantable Infusion Pump inAmbulatory Patients with Recurrent Venous Thrombosis,” Surgery88:507-516 (1980); and Saudek et al., “A Preliminary Trial of theProgrammable Implantable Medication System for Insulin Delivery,” NewEngl. J. Med. 321:574-579 (1989)). In another embodiment, polymericmaterials can be used (see Goodson; Smolen et al., “Drug Product Designand Performance,” Controlled Drug Bioavailability Vol. 1, John Wiley andSons, New York (1984); Langer et al., “Chemical and Physical Structureof Polymers as Carriers for Controlled Release of Bioactive Agents: AReview,” J. Macromol. Sci. Rev. Macromol. Chem. C23(1):61-126 (1983);Levy et al., “Inhibition of Calcification of Bioprosthetic Heart Valvesby Local Controlled-Release Diphosphonate,” Science 228:190-192 (1985);During et al., “Controlled Release of Dopamine from a Polymeric BrainImplant: In Vivo Characterization,” Ann. Neurol. 25:351-356 (1989); andHoward et al., “Intracerebral drug delivery in rats with lesion-inducedmemory deficits,” J. Neurosurg. 71:105-112 (1989)).

Such dosage forms can be used to provide controlled- orsustained-release of one or more active ingredients using, for example,hydropropylmethyl cellulose, ethylcellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, multiparticulates, liposomes, microspheres, or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled- or sustained-release formulationsknown to those in the art, including those described herein, can bereadily selected for use with the active ingredients of the disclosure.The disclosure thus encompasses single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled- orsustained-release.

The compositions can optionally, but preferably, further comprise asuitable amount of a pharmaceutically acceptable excipient so as toprovide the form for proper administration to the animal Such apharmaceutical excipient can be a diluent, suspending agent,solubilizer, binder, disintegrant, preservative, coloring agent,lubricant, and the like. The pharmaceutical excipient can be a liquid,such as water or an oil, including those of petroleum, animal,vegetable, or synthetic origin, such as peanut oil, soybean oil, mineraloil, sesame oil, and the like. The pharmaceutical excipient can besaline, gum acacia, gelatin, starch paste, talc, keratin, colloidalsilica, urea, and the like. In addition, auxiliary, stabilizing,thickening, lubricating, and coloring agents can be used. In oneembodiment, the pharmaceutically acceptable excipient is sterile whenadministered to an animal Water is a particularly useful excipient whena compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid excipients, particularly for injectable solutions.Suitable pharmaceutical excipients also include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. Thecompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, (Amer. Pharmaceutical Ass'n, Washington, D C,1986), incorporated herein by reference. Other examples of suitablepharmaceutical excipients are described by Radebough et al.,“Preformulation,” pp. 1447-1676 in Remington's Pharmaceutical SciencesVol. 2 (Gennaro, ed., 19^(th) Ed., Mack Publishing, Easton, Pa., 1995),incorporated herein by reference.

The compositions can take the form of solutions, suspensions, emulsions,tablets such as an orally disintegrating tablet (ODT) or a sublingualtablet, pills, pellets, capsules, capsules containing liquids, powders,sustained-release formulations, suppositories, emulsions, aerosols,sprays, suspensions, microparticles, multiparticulates, rapidlydissolving films or other forms for oral or mucosal administration, orany other form suitable for use. In one embodiment, the composition isin the form of an ODT (see, e.g., U.S. Pat. Nos. 7,749,533 and9,241,910). In another embodiment, the composition is in the form of asublingual tablet (see, e.g., U.S. Pat. Nos. 6,572,891 and 9,308,175).In another embodiment, the composition is in the form of a capsule (see,e.g., U.S. Pat. No. 5,698,155). In another embodiment, the compositionis in a form suitable for buccal administration, e.g., as a tablet,lozenge, gel, patch, or film, formulated in a conventional manner (see,e.g., Pather et al., “Current status and the future of buccal drugdelivery systems,” Expert Opin. Drug Deliv. 5(5):531-542 (2008)). Inanother embodiment, the composition is in a form suitable for gingivaladministration, e.g., as a polymeric film comprising polyvinyl alcohol,chitosan, polycarbophil, hydroxypropylcellulose, or Eudragit S-100, asdisclosed by Padula et al., “In Vitro Evaluation of Mucoadhesive Filmsfor Gingival Administration of Lidocaine,” AAPS PharmSciTech14(4):1279-1283 (2013). In another embodiment, the composition is in aform suitable for intraocular administration.

In one embodiment, the compounds of formula (1), (1A), (1B), or (1C) ora pharmaceutically acceptable salt or solvate thereof, or the compoundsof formula (1D), (1E), or (1F) or a solvate thereof are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. A compound of formula (1), (1A), (1B),or (1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof to beorally delivered can be in the form of tablets, capsules, gelcaps,caplets, lozenges, aqueous or oily solutions, suspensions, granules,microparticles, multiparticulates, powders, emulsions, syrups, orelixirs, for example. When a compound of formula (1), (1A), (1B), or(1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof isincorporated into oral tablets, such tablets can be compressed, tablettriturates, enteric-coated, sugar-coated, film-coated, multiplycompressed, or multiply layered. Techniques and compositions for makingsolid oral dosage forms are described in Pharmaceutical Dosage Forms:Tablets (Lieberman et al., eds., 2^(nd) Ed., Marcel Dekker, Inc., 1989and 1990). Techniques and compositions for making tablets (compressedand molded), capsules (hard and soft gelatin) and pills are alsodescribed by King, “Tablets, Capsules, and Pills,” pp. 1553-1593 inRemington's Pharmaceutical Sciences (Osol, ed., 16^(th) Ed., MackPublishing, Easton, Pa., 1980).

Liquid oral dosage forms include aqueous and nonaqueous solutions,emulsions, suspensions, and solutions and/or suspensions reconstitutedfrom non-effervescent granules, optionally containing one or moresuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, flavoring agents, and the like.Techniques and composition for making liquid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman etal., eds., 2^(nd) Ed., Marcel Dekker, Inc., 1996 and 1998).

An orally administered compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof can contain one or moreagents, for example, sweetening agents such as fructose, aspartame orsaccharin; flavoring agents such as peppermint, oil of wintergreen, orcherry; coloring agents; and preserving agents, to provide apharmaceutically palatable preparation. Moreover, where in tablet orpill form, the compositions can be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compositions. In these latter platforms, fluid fromthe environment surrounding the capsule is imbibed by the drivingcompound, which swells to displace the agent or agent compositionthrough an aperture. These delivery platforms can provide an essentiallyzero order delivery profile as opposed to the spiked profiles ofimmediate release formulations. A time-delay material such as glycerolmonostearate or glycerol stearate can also be used. Oral compositionscan include standard excipients such as mannitol, lactose, starch,magnesium stearate, sodium saccharin, cellulose, and magnesiumcarbonate. In one embodiment, the excipients are of pharmaceuticalgrade.

When a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof is to be injectedparenterally, it can be, e.g., in the form of an isotonic sterilesolution. Alternatively, when a compound of formula (1), (1A), (1B), or(1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof is to beinhaled, it can be formulated into a dry aerosol or can be formulatedinto an aqueous or partially aqueous solution.

In another embodiment, the compounds of formula (1), (1A), (1B), or (1C)or a pharmaceutically acceptable salt or solvate thereof, or thecompounds of formula (1D), (1E), or (1F) or a solvate thereof can beformulated for intravenous administration. In certain embodiments,compositions for intravenous administration comprise sterile isotonicaqueous buffer. Where necessary, the compositions can also include asolubilizing agent. A compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof for intravenousadministration can optionally include a local anesthetic such asbenzocaine or prilocaine to lessen pain at the site of the injection.Generally, the ingredients are supplied either separately or mixedtogether in unit dosage form, for example, as a dry lyophilized powderor water free concentrate in a hermetically sealed container such as anampule or sachette indicating the quantity of active agent. Where acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof is to be administered by infusion, it canbe dispensed, for example, with an infusion bottle containing sterilepharmaceutical grade water or saline. Where a compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof is administered by injection, an ampule of sterile water forinjection or saline can be provided so that the ingredients can be mixedprior to administration.

The amount of the compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or the compound offormula (1D), (1E), or (1F) or a solvate thereof that is effective forthe treatment or prevention of a Condition can be determined by standardclinical techniques. In addition, in vitro and/or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on, e.g., the route ofadministration and the seriousness of the Condition, and can be decidedaccording to the judgment of a practitioner and/or each animal'scircumstances. In other examples thereof, variations will necessarilyoccur depending upon the weight and physical condition (e.g., hepaticand renal function) of the animal being treated, the disorder to betreated, the severity of the symptoms, the frequency of the dosageinterval, the presence of any deleterious side-effects, and theparticular compound utilized, among other things.

Suitable effective dosage amounts of the compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or the compound of formula (1D), (1E), or (1F) or a solvate thereof arefrom about 0.0002 mg/kg to about 25 mg/kg of body weight of the animalper day in one embodiment, from about 0.00025 mg/kg/day to about 20mg/kg/day in another embodiment, from about 15 mg/kg/day to about 600mg/kg/day in another embodiment, from about 20 mg/kg/day to about 600mg/kg/day in another embodiment, from about 25 mg/kg/day to about 600mg/kg/day in another embodiment, and from about 30 mg/kg/day to about600 mg/kg/day in another embodiment. In another embodiment, theeffective dosage amount is about 10.0 mg/kg/day or less. In certainembodiments, suitable effective dosage amounts of the compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltor solvate thereof, or the compound of formula (1D), (1E), or (1F) or asolvate thereof are from about 0.0002 mg/kg/day to about 10 mg/kg/day,from about 0.001 mg/kg/day to about 10 mg/kg/day, from about 0.002mg/kg/day to about 10 mg/kg/day, from about 0.003 mg/kg/day to about 10mg/kg/day, from about 0.0005 mg/kg/day to about 5.0 mg/kg/day, fromabout 0.001 mg/kg/day to about 2.5 mg/kg/day, from about 0.002 mg/kg/dayto about 2.0 mg/kg/day, or from about 0.002 mg/kg/day to about 1.0mg/kg/day. In another embodiment, the effective dosage amount is about1.0 mg/kg/day or less. In certain other embodiments, suitable effectivedosage amounts of the compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or the compound offormula (1D), (1E), or (1F) or a solvate thereof are from about 0.001mg/kg/day to about 1.0 mg/kg/day, from about 0.002 mg/kg/day to about0.8 mg/kg/day, from about 0.0025 mg/kg/day to about 0.5 mg/kg/day, fromabout 0.003 mg/kg/day to about 0.15 mg/kg/day, from about 0.006mg/kg/day to about 0.12 mg/kg/day, or from about 0.010 mg/kg/day toabout 0.10 mg/kg/day. It is to be understood that for these dosageamounts, the term “day” means a 24 hour cycle beginning at the time ofadministration of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof. For example, for anordinary overnight sleep cycle, if a compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or a compound of formula (1D), (1E), or (1F) or a solvate thereof isadministered at 9:30 PM, then that “day” ends at 9:29 PM on thefollowing calendar day. In another example, for a shift-worker's sleepcycle, if a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof is administered at 8:15AM, then that “day” ends at 8:14 AM on the following calendar day.

A suitable effective dosage amount of the compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or the compound of formula (1D), (1E), or (1F) or a solvate thereofadministered as a single dose is from about 0.06 mg to about 600 mg,from about 0.05 mg to about 50 mg, from about 0.12 mg to about 600 mg,from about 0.10 mg to about 30 mg, from about 0.10 mg to about 20 mg,from about 0.10 mg to about 15 mg, from about 0.10 mg to about 10 mg,from about 0.10 mg to about 8 mg, from about 0.10 mg to about 7 mg, fromabout 0.15 mg to about 30 mg, from about 0.15 mg to about 20 mg, fromabout 0.15 mg to about 15 mg, from about 0.15 mg to about 10 mg, fromabout 0.15 mg to about 8 mg, from about 0.15 mg to about 7 mg, fromabout 0.18 mg to about 9 mg, from about 0.18 mg to about 6 mg, fromabout 0.18 mg to about 4.0 mg, from about 0.2 mg to about 30 mg, fromabout 0.2 mg to about 20 mg, from about 0.2 mg to about 15 mg, fromabout 0.2 mg to about 10 mg, from about 0.2 mg to about 8 mg, from about0.2 mg to about 7 mg, from about 0.2 mg to about 6.0 mg, from about 0.2mg to about 4.0 mg, from about 0.2 mg to about 3.0 mg, from about 0.2 mgto about 2.0 mg, from about 0.2 mg to about 1.0 mg, from about 0.5 mg toabout 6.0 mg, from about 0.5 mg to about 4.0 mg, from about 0.5 mg toabout 3.0 mg, from about 0.5 mg to about 2.0 mg, from about 0.5 mg toabout 1.0 mg, from about 0.6 mg to about 6.0 mg, or from about 0.6 mg toabout 4.0 mg, although it is, in certain embodiments, about 0.05 mg,about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.100mg, about 0.120 mg, about 0.125 mg, about 0.150 mg, about 0.175 mg,about 0.200 mg, about 0.225 mg, about 0.250 mg, about 0.275 mg, about0.30 mg, about 0.35 mg, about 0.40 mg, about 0.45 mg, about 0.50 mg,about 0.55 mg, about 0.60 mg, about 0.65 mg, about 0.70 mg, about 0.75mg, about 0.80 mg, about 0.85 mg, about 0.90 mg, about 0.95 mg, about1.00 mg, about 1.25 mg, about 1.50 mg, about 1.75 mg, about 2.00 mg,about 2.25 mg, about 2.50 mg, about 2.75 mg, about 3.00 mg, about 3.25mg, about 3.50 mg, about 3.75 mg, about 4.0 mg, about 4.5 mg, about 5.0mg, about 5.5 mg, about 6.0 mg, about 6.5 mg, about 7.0 mg, about 7.5mg, about 8.0 mg, about 9.0 mg, about 10 mg, about 12 mg, about 12.5 mg,about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about50 mg, about 70 mg, about 100 mg, about 120 mg, about 150 mg, about 175mg, or about 200 mg. As known to those in the art, for a human animal, asingle daily dose (in mg) can be converted to a mg/kg/day dosage amountby dividing the mg dose by 60 kg, the art-recognized average mass of ahuman animal. For example, a single daily human dose of 1.25 mg isso-converted to a dosage amount of about 0.021 mg/kg/day.

The effective dosage amounts described herein refer to total amountsadministered; that is, if more than one compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or more than one compound of formula (1D), (1E), or (1F) or a solvatethereof is administered, the effective dosage amounts correspond to thetotal amount administered.

Administration can be as a single dose or as a divided dose. In oneembodiment, an effective dose or dosage amount is administered only asneeded (pro re nata) such as, for example, in the event that sleepcannot readily be achieved, or upon middle-of-the night awakeningfollowed by failure to readily return to sleep. In another embodiment,an effective dose or dosage amount is administered about every 24 hours,for example, in preparation for sleep, until the Condition is abated. Inanother embodiment, a single effective dose or dosage amount isadministered in preparation for sleep to abate the Condition. In anotherembodiment, a single effective dose or dosage amount is administered inpreparation for sleep on two consecutive days to abate the Condition. Inanother embodiment, a single effective dose or dosage amount isadministered in preparation for sleep on three consecutive days to abatethe Condition. In another embodiment, a single effective dose or dosageamount is administered in preparation for sleep on four consecutive daysto abate the Condition. In another embodiment, a single effective doseor dosage amount is administered in preparation for sleep on fiveconsecutive days to abate the Condition. In another embodiment, a singleeffective dose or dosage amount is administered in preparation for sleepon six consecutive days to abate the Condition. In another embodiment, asingle effective dose or dosage amount is administered in preparationfor sleep on seven consecutive days to abate the Condition. In anotherembodiment, a single effective dose or dosage amount is administered inpreparation for sleep on eight consecutive days to abate the Condition.In another embodiment, a single effective dose or dosage amount isadministered in preparation for sleep on nine consecutive days to abatethe Condition. In another embodiment, a single effective dose or dosageamount is administered in preparation for sleep on 10 consecutive daysto abate the Condition. In another embodiment, a single effective doseor dosage amount is administered in preparation for sleep on up to 12consecutive days to abate the Condition. In another embodiment, a singleeffective dose or dosage amount is administered in preparation for sleepon 12 consecutive days to abate the Condition. In another embodiment, asingle effective dose or dosage amount is administered in preparationfor sleep on up to 14 consecutive days to abate the Condition. Inanother embodiment, a single effective dose or dosage amount isadministered in preparation for sleep on 14 consecutive days to abatethe Condition. In another embodiment, a single effective dose or dosageamount is administered in preparation for sleep on up to 21 consecutivedays to abate the Condition. In another embodiment, a single effectivedose or dosage amount is administered in preparation for sleep on 21consecutive days to abate the Condition. In another embodiment, a singleeffective dose or dosage amount is administered in preparation for sleepon up to 28 consecutive days to abate the Condition. In anotherembodiment, a single effective dose or dosage amount is administered inpreparation for sleep on 28 consecutive days to abate the Condition. Inanother embodiment, a single effective dose or dosage amount isadministered in preparation for sleep on at least 28 consecutive days toabate the Condition.

In one embodiment, an effective dose or dosage amount is administeredabout 60 minutes before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 45minutes before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 30minutes before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 20minutes before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 20minutes or less before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 15minutes before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 15minutes or less before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 10minutes before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 10minutes or less before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 5minutes before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 5minutes or less before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 2minutes before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 2minutes or less before an animal's median habitual bedtime. In anotherembodiment, an effective dose or dosage amount is administered about 1minute before an animal's median habitual bedtime.

In one embodiment, a composition comprising a compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof, in accordance with the disclosure is used as a medicament. Inanother embodiment, compositions comprising a compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof, are disclosed which can be used for preparing a medicamentcontaining said compositions.

In another embodiment, a composition comprising a compound of formula(1), (1A), (1B), or (1C) or a pharmaceutically acceptable salt orsolvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, is useful as a medicament in the treatment orprevention of a sleep disorder. In another embodiment, a compositioncomprising a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, is useful as amedicament in the treatment or prevention of a sleep disorder where thesleep disorder is an insomnia condition, a hypersomnia condition, acircadian rhythm sleep-wake disorder, an alcohol-induced sleep disorder,or any combination thereof.

In another embodiment, a composition comprising a compound of formula(1), (1A), (1B), or (1C) or a pharmaceutically acceptable salt orsolvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, is useful as a medicament in the treatment of a sleepdisorder. In another embodiment, a composition comprising a compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltor solvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, is useful as a medicament in the treatment of a sleepdisorder where the sleep disorder is an insomnia condition, ahypersomnia condition, a circadian rhythm sleep-wake disorder, analcohol-induced sleep disorder, or any combination thereof.

In another embodiment, a composition comprising a compound of formula(1), (1A), (1B), or (1C) or a pharmaceutically acceptable salt orsolvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, is useful as a medicament in the prevention of a sleepdisorder. In another embodiment, a composition comprising a compound offormula (1), (1A), (1B), or (1C) or a pharmaceutically acceptable saltor solvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, is useful as a medicament in the prevention of a sleepdisorder where the sleep disorder is an insomnia condition, ahypersomnia condition, a circadian rhythm sleep-wake disorder, analcohol-induced sleep disorder, or any combination thereof.

In another embodiment, a composition comprising a compound of formula(1), (1A), (1B), or (1C) or a pharmaceutically acceptable salt orsolvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, is useful as a medicament in the treatment orprevention of an insomnia condition. In another embodiment, acomposition comprising a compound of formula (1), (1A), (1B), or (1C) ora pharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, is useful as amedicament in the treatment of an insomnia condition. In anotherembodiment, a composition comprising a compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or a compound of formula (1D), (1E), or (1F) or a solvate thereof, isuseful as a medicament in the prevention of an insomnia condition.

In another embodiment, a composition comprising a compound of formula(1), (1A), (1B), or (1C) or a pharmaceutically acceptable salt orsolvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, is useful as a medicament in the treatment orprevention of an alcohol-induced sleep disorder. In another embodiment,a composition comprising a compound of formula (1), (1A), (1B), or (1C)or a pharmaceutically acceptable salt or solvate thereof, or a compoundof formula (1D), (1E), or (1F) or a solvate thereof, is useful as amedicament in the treatment of an alcohol-induced sleep disorder. Inanother embodiment, a composition comprising a compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof, is useful as a medicament in the prevention of analcohol-induced sleep disorder.

For any of these uses, the composition comprising a compound of formula(1), (1A), (1B), or (1C) or a pharmaceutically acceptable salt orsolvate thereof, or a compound of formula (1D), (1E), or (1F) or asolvate thereof, can further comprise a second therapeutic agent in themedicament.

The methods for treating or preventing a Condition in an animal in needthereof can further comprise co-administering to the animal beingadministered a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof (i.e., a firsttherapeutic agent) a second therapeutic agent. In one embodiment, thesecond therapeutic agent is administered in an effective amount.

An effective amount of the second therapeutic agent will be known tothose skilled the art depending on the agent. However, it is well withinthe skilled artisan's purview to determine the second therapeuticagent's optimal effective-amount range in view of the presentdisclosure. A compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof and the secondtherapeutic agent combined can act either additively or synergisticallyto treat the same Condition, or they may act independently of each othersuch that the compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or the compound offormula (1D), (1E), or (1F) or a solvate thereof treats or prevents aCondition and the second therapeutic agent treats or prevents anotherdisorder, which can be the same as or different from the Condition. Inone embodiment of the disclosure, where a second therapeutic agent isco-administered to an animal for treatment of a Condition (e.g., a sleepdisorder), the minimal effective amount of the compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or the compound of formula (1D), (1E), or (1F) or a solvatethereof can be less than its minimal effective amount would be where thesecond therapeutic agent is not administered. In this embodiment, thecompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or the compound of formula (1D),(1E), or (1F) or a solvate thereof and the second therapeutic agent canact synergistically to treat or prevent a Condition.

In one embodiment, a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof is administeredconcurrently with a second therapeutic agent as a single compositioncomprising an effective amount of a compound of formula (1), (1A), (1B),or (1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof and aneffective amount of the second therapeutic agent. Alternatively, acomposition comprising an effective amount of a compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or a compound of formula (1D), (1E), or (1F) or a solvatethereof and a second composition comprising an effective amount of thesecond therapeutic agent are concurrently administered. In anotherembodiment, an effective amount of a compound of formula (1), (1A),(1B), or (1C) or a pharmaceutically acceptable salt or solvate thereof,or a compound of formula (1D), (1E), or (1F) or a solvate thereof isadministered prior or subsequent to administration of an effectiveamount of the second therapeutic agent. In this embodiment, the compoundof formula (1), (1A), (1B), or (1C) or a pharmaceutically acceptablesalt or solvate thereof, or the compound of formula (1D), (1E), or (1F)or a solvate thereof is administered while the second therapeutic agentexerts its therapeutic effect, or the second therapeutic agent isadministered while the compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or the compound offormula (1D), (1E), or (1F) or a solvate thereof exerts its therapeuticeffect for treating or preventing a Condition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a second sedative or hypnotic, a Cox-IIinhibitor, a 5-lipoxygenase inhibitor, an anti-emetic, a β-adrenergicblocker, an anticonvulsant, an antidepressant, a Ca²⁺-channel blocker,an anti-cancer agent, an agent for treating or preventing UI, an agentfor treating or preventing anxiety, an agent for treating or preventinga memory disorder, an agent for treating or preventing obesity, an agentfor treating or preventing constipation, an agent for treating orpreventing cough, an agent for treating or preventing diarrhea, an agentfor treating or preventing high blood pressure, an agent for treating orpreventing epilepsy, an agent for treating or preventinganorexia/cachexia, an agent for treating or preventing drug abuse, anagent for treating or preventing an ulcer, an agent for treating orpreventing IBD, an agent for treating or preventing IBS, an agent fortreating or preventing addictive disorder, an agent for treating orpreventing Parkinson's disease and parkinsonism, an agent for treatingor preventing a stroke, an agent for treating or preventing a seizure,an agent for treating or preventing a pruritic condition, an agent fortreating or preventing psychosis, an agent for treating or preventingHuntington's chorea, an agent for treating or preventing ALS, an agentfor treating or preventing a cognitive disorder, an agent for treatingor preventing a migraine, an agent for inhibiting vomiting, an agent fortreating or preventing dyskinesia, an agent for treating or preventingdepression, or any mixture thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts or solvates thereof, or anymixture thereof.

In certain embodiments, the opioid agonist is codeine, hydromorphone,hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine,tramadol, oxymorphone, pharmaceutically acceptable salts or solvatesthereof, or any mixture thereof.

Examples of useful non-opioid analgesics include, but are not limitedto, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,a pharmaceutically acceptable salt thereof, or any mixture thereof.Other suitable non-opioid analgesics include the following,non-limiting, chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs; salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);alkanones, including nabumetone; a pharmaceutically acceptable saltthereof; or any mixture thereof. For a more detailed description of theNSAIDs, see Insel, “Analgesic-Antipyretic and Anti-inflammatory Agentsand Drugs Employed in the Treatment of Gout,” pp. 617-657 in Goodman andGilman's The Pharmacological Basis of Therapeutics (Goodman et al.,eds., 9^(th) Ed., McGraw-Hill, New York 1996), and Hanson, “Analgesic,Antipyretic and Anti-Inflammatory Drugs,” pp. 1196-1221 in Remington:The Science and Practice of Pharmacy Vol. II (Gennaro, ed., 19^(th) Ed.,Mack Publishing, Easton, Pa., 1995), which are hereby incorporated byreference in their entireties.

Examples of useful second sedatives or hypnotics include, but are notlimited to, benzodiazepines, including lorazepam, temazepam, andtriazolam; barbiturates, including phenobarbital, pentobarbital, andsecobarbital; so-called “z-drugs,” including zaleplon, zolpidem, andzopiclone; ramelteon; suvorexant; a pharmaceutically acceptable saltthereof, or any mixture thereof.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, celecoxib,DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone,nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522,RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367,SC-5766, PD-164387, etoricoxib, valdecoxib, parecoxib, apharmaceutically acceptable salt thereof, or any mixture thereof.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, a pharmaceutically acceptable salt thereof, or any mixturethereof.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin,zonisamide, a pharmaceutically acceptable salt thereof, or any mixturethereof.

Examples of useful Ca²⁺-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, perhexiline, a pharmaceuticallyacceptable salt thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, dicyclomine, a pharmaceutically acceptable salt thereof, orany mixture thereof.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; propanediolcarbamates, such as meprobamate and tybamate; a pharmaceuticallyacceptable salt thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingdiarrhea include, but are not limited to, diphenoxylate, loperamide, apharmaceutically acceptable salt thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, benzodiazepines, γ vinyl GABA, acetazolamide,felbamate, a pharmaceutically acceptable salt thereof, or any mixturethereof.

Examples of useful therapeutic agents for treating or preventing drugabuse include, but are not limited to, methadone, desipramine,amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, serotoninantagonists, a pharmaceutically acceptable salt thereof, or any mixturethereof.

Examples of non-steroidal anti-inflammatory agents, 5-lipoxygenaseinhibitors, anti-emetics, β-adrenergic blockers, antidepressants, andanti-cancer agents are known in the art and can be selected by thoseskilled in the art. Examples of useful therapeutic agents for treatingor preventing memory disorder, obesity, constipation, cough, high bloodpressure, anorexia/cachexia, an ulcer, IBD, IBS, addictive disorder,Parkinson's disease and parkinsonism, a stroke, a seizure, a pruriticcondition, psychosis, Huntington's chorea, ALS, a cognitive disorder, amigraine, dyskinesia, depression, and/or treating, preventing orinhibiting vomiting include those that are known in the art and can beselected by those skilled in the art.

A composition of the disclosure is prepared by a method comprisingadmixing a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof, with apharmaceutically acceptable carrier or excipient. Admixing can beaccomplished using methods known for admixing a compound (or derivative)and a pharmaceutically acceptable carrier or excipient. In oneembodiment, the compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or the compound offormula (1D), (1E), or (1F) or a solvate thereof is present in thecomposition in an effective amount.

5.7 Kits

The disclosure further provides kits that can simplify the handling andadministration of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof to an animal.

A typical kit of the disclosure comprises a unit dosage form of acompound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof. In one embodiment, the unit dosage formcomprises a first container, which can be sterile, containing aneffective amount of a compound of formula (1), (1A), (1B), or (1C) or apharmaceutically acceptable salt or solvate thereof, or a compound offormula (1D), (1E), or (1F) or a solvate thereof and a pharmaceuticallyacceptable carrier or excipient. The kit can further comprise a label orprinted instructions instructing the use of the compound of formula (1),(1A), (1B), or (1C) or a pharmaceutically acceptable salt or solvatethereof, or the compound of formula (1D), (1E), or (1F) or a solvatethereof to treat or prevent a Condition. The kit can further comprise aunit dosage form of a second therapeutic agent, for example, a secondcontainer containing an effective amount of the second therapeutic agentand a pharmaceutically acceptable carrier or excipient. In anotherembodiment, the kit comprises a container containing an effective amountof a compound of formula (1), (1A), (1B), or (1C) or a pharmaceuticallyacceptable salt or solvate thereof, or a compound of formula (1D), (1E),or (1F) or a solvate thereof, an effective amount of a secondtherapeutic agent and a pharmaceutically acceptable carrier orexcipient. Examples of second therapeutic agents include, but are notlimited to, those listed above.

Kits of the disclosure can further comprise a device useful foradministering the unit dosage form. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

5.8 Other Compounds

Other compounds referred to herein include:

The synthesis (Example 9, columns 103-108) and certain pertinentproperties (Example 18, columns 116-117) of Compound 405 are disclosedin, inter alia, U.S. Pat. No. 8,476,271, which is hereby incorporated byreference in its entirety. Compound 405K is the mono-potassium salt ofCompound 405; it was prepared by a method known to those in the art. Thesynthesis (Example 18, column 20) and certain properties (ExperimentalExamples 1-3 and 5, columns 22-22) of Compound W-212393 are disclosedin, inter alia, U.S. Pat. No. 7,566,728, which is hereby incorporated byreference in its entirety. Throughout the examples in this application,the free base, i.e., the non-salt form, of Compound W-212393 was used.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, that would be within the purview of those skilled inthe art, and changes in formulation or changes in experimental design,are to be considered to fall within the scope of the inventionincorporated herein.

6. EXAMPLES

Certain Examples below relate to methods for treating or preventing asleep disorder by administering a compound of formula (1), (1A), (1B),or (1C) or a pharmaceutically acceptable salt or solvate thereof, or acompound of formula (1D), (1E), or (1F) or a solvate thereof to ananimal in need of such treatment.

6.1 Example 1: Human Trial Protocol

A phase 1, randomized, double-blind, single-center, crossover, in- andout-patient study assessing the effects of Compound (1D) on sleepefficiency (“SE”), Latency to Persistent Sleep (“LPS”), Wake After SleepOnset (“WASO”), and Total Sleep Time (“TST”) in subjects with insomniadisorder was performed. The study randomized up to about 40 subjects inorder to achieve about 24 completers (i.e., subjects who completed bothDosing Periods 1 and 2). The subjects included males and females aged 18to 60 years, inclusive, with insomnia disorder (as defined by theDiagnostic and Statistical Manual of Mental Disorders, Fifth Edition,American Psychiatric Association Publishing, Arlington, Va. (2013)(“DSM-5”)) and who otherwise had no significant medical or psychiatrichistory.

This study used two consecutive dosing nights of orally administeredCompound (1D) or placebo in each of two separate dosing periods (DosingPeriods 1 and 2) that were approximately five days apart during a10-day-long treatment period. Compound (1D) was administered orally inan aqueous suspension comprising 0.5% w/w methylcellulose (METHOCEL A4CPremium, Dow Chemical Co., Midland, Mich.). A 10 mg dose was achieved byadministering from a dosing vial the suspension of Compound (1D)followed by four or more sterile-water irrigation rinses (20 mL perrinse) of the dosing vial and sufficient water to total 240 mL, witheach subject dosed 30 minutes before their median habitual bedtime.Placebo to match the Compound (1D) aqueous suspension was orallyadministered in the same way. The placebo consisted of an aqueoussuspension of corn starch (UNI-PURE FL, Ingredion Germany GmbH, Hamburg,Germany) also comprising 0.5% w/w methylcellulose (METHOCEL A4CPremium).

The study consisted of three periods: (1) pre-randomization (up to 28days), (2) treatment (10 days), and (3) follow-up.

(1) The pre-randomization period protocol consisted of a screening visitfollowed, for successful subjects, by a baseline visit, each describedin more detail as follows.

During a screening visit (Days −28 to −8), vital signs, medical, sleepand psychiatric histories, laboratory test results, pregnancy testresults, drug screen results, Colombia-suicide severity rating scale(“C-SSRS”) assessment, and an ECG were obtained. If a washout ofprohibited medications was required, this washout was completed duringthe screening. Subjects who successfully completed the screening visitreceived a sleep-habits diary that was completed for a minimum of sevenconsecutive days before the baseline visit so that median habitualbedtime could be assessed.

During a baseline visit (Days −7 to −5), subjects arrived at a clinicalunit in the afternoon or evening of Day −7. At that time, they began astay of two consecutive nights during which each subject underwentcontinuous PSG recording for eight hours on the first night (Night 1) toassess eligibility criteria and to screen out subjects with sleep apneaor periodic limb movements with arousal. Successful subjects underwentanother eight hours of continuous PSG recording on the second night(Night 2), which determined if a subject met the sleep-eligibilitycriteria based on the average of data obtained on Nights 1 and 2 of thebaseline period. During the baseline visits, subjects also practiced thepsychometric tests used in this study (e.g., digital symbol substitutiontest (“DSST”), psychomotor vigilance task (“PVT”), and KarolinksaSleepiness Scale (“KS S”)) and familiarized themselves with the profileof mood states-standard (“POMS-standard”) and post-sleep questionnaire.To assess a subject's perception of the quality and quantity of sleep,the post-sleep questionnaire asked questions such as “how many minutesdid it take you to fall asleep last night after you got into bed and thelights were turned off?”, “how many times did you awaken during thenight?”, and “on a scale from 1 to 10, with 1 being poor and 10 beingexcellent, how would you rate the quality of your sleep last night?”.Subjects who met all eligibility criteria after the baseline visitreturned approximately seven days later to enter the treatment period(Dosing Periods 1 and 2).

A summary of the PSG recording procedure that was used is as follows.Standard placements for EEG electrodes were derived according to theinternational 10-20 system (see, e.g., Jasper, “The ten-twenty electrodesystem of the international federation,” Electroencephalography Clin.Neurophys. 10:371-375 (1958)) with the exception of the change of theA1-A2 labels to M1-M2, pursuant to the AASM Manual for Scoring of Sleep(Berry et al., “The AASM Manual for the Scoring of Sleep and AssociatedEvents: Rules, Terminology and Technical Specifications,” Version 2.0.3,American Academy of Sleep Medicine, Darien, Ill., (2014)). This systemrequires that electrodes be positioned in measured relationships tolandmark anatomical points. Standard placements for EOG, submental EMGelectrodes, anterior tibialis EMG electrodes, and airflow sensors wereconsistent with the AASM Manual for Scoring of Sleep.

Electrodes used for EEG recording were standard gold- or silver-cupelectrodes intended for use in EEG recording. These electrodes wereapproximately 4 to 10 mm. in diameter and were connected to a thin wirehaving an appropriate connector. Electrodes used for EOG and EMGrecordings were self-adhesive electrodes of approximately 12 mm diameterwith snap-on connectors that enabled the electrode to be connected to athin wire having an appropriate connector. Electrodes used for ECGrecordings were self-adhesive electrodes of approximately 12 mm.diameter with snap-on connectors that enabled the electrode to beconnected to a thin wire having an appropriate connector (e.g., 3M REDDOT electrodes or MEDITRACE electrodes).

Scalp and skin surfaces at points of contact with an electrode werethoroughly cleansed prior to electrode placement by applying a mildabrasive cleanser on both scalp and skin surfaces according tomanufacturers' recommendations using a cotton swab. Isopropyl alcoholwas used to wipe the abraded surface. A small dab of conductive EEGpaste was then applied to the scalp or skin surface and to the cupelectrodes. When facial or body hair was present at a desired site, ifan insignificant deviation from the required electrode placement waspossible an electrode was relocated to an adjacent area, otherwise, thefacial or body hair was removed.

The electrical impedance of all EEG, EOG, submental EMG, limb EMG, andECG electrodes was less than 5 kOhms; electrical impedance was checkedprior to the start of recording using a commercially-available impedancemeter. Digital PSG systems were calibrated prior to each PSG recordingperformed 45 minutes prior to “lights-off.” Calibration involved the useof internally generated input signals of known voltage, which served asbenchmarks against which physiological data were measured andquantified. The digital PSG calibration settings were as follows:

Low High Frequency Frequency Channel Filter (Hz) Filter (Hz) EOG 0.3 35EMG 10 70 to 120 EEG 0.3 35 ECG 0.3 70 Airflow 0.1 15Acquisition of EEG signals occurred at a minimum sampling rate that wasapproximately three times the high-frequency filter setting.Specifically, the minimum sampling rate for EEGs collected using thehigh-frequency filter setting specified was at least 100 samples persecond, or 100 Hz. No sampling rate greater than 256 Hz was used. Theminimum storage rate for all PSG data was 200 Hz.

Biological calibration or “biocalibration” is a procedure in which thesubject, in bed and supine, lies awake quietly and performs specificactions or movements in a specified sequence so that the quality of PSGsignals may be assessed. Biocalibration was performed 15 minutes beforelights-off. However, immediately following the completion ofbiocalibration procedures, the subject was awake and instructed to situp to leave a reasonable time for “settling” before lights-off. Subjectswere instructed not to move their heads or bodies unnecessarily whilebiocalibration procedures were performed so that head or body movementdid not result in an artifact that obscured a biocalibration signal.Biocalibration procedures were performed on PSG nights according to thefollowing schedule:

Instruction to Biocalibration Subject Duration Nights “Rest with your 30sec. of artifact- All eyes closed” free tracing “Rest with your 30 sec.of artifact- All eyes open” free tracing “Open your eyes,” 1 min. All“close your eyes” (30 sec. each) “Open your eyes” 5 sec. All “Look up,”Several times during All “look down” a 30 sec. period “Open your eyes” 5sec. All “Glance to the left,” Several times during All “glance to theright” a 30 second period “Grit your teeth,” 5 to 10 sec. All “stick outyour tongue,” “stick out your jaw” “Breathe in and out 15 sec. Screeningthrough your Nights mouth” “Breathe in and out 15 sec. Screening throughyour Nights nose” “Hold your 5 sec. Screening breath” Nights “Flex yourleft 5 to 10 sec. Screening toe/leg” Nights “Flex your right 5 to 10sec. Screening toe/leg” Nights

A PSG “screening montage” of 18 channels of recording displayed in aspecific sequence was used for Night 1. A “treatment montage” of 12channels of recording displayed in a specific sequence was used forNight 2 and treatment nights. The following electrode derivations orpositions were eliminated from the screening montage to yield thetreatment montage: left anterior tibialis, right anterior tibialis,nasal/oral airflow (thermistor), nasal airflow (nasal pressuretransducer), respiratory inductance plethysomography, and respiratoryinductance plethysomography.

(2) The 10-day treatment period included two dosing periods (DosingPeriods 1 and 2) that were approximately 5 days apart. Once continuedeligibility was confirmed, subjects were randomized as to treatment uponcheck-in on Day 1. Each of Dosing Period 1 (Days 1 to 3) and DosingPeriod 2 (Days 8 to 10) consisted of a stay of two consecutive nights,during which subjects received the same study drug (either Compound (1D)or placebo) on both evenings of that dosing period. The study drug wasadministered 30 minutes before each subject's median habitual bedtime(to the nearest quarter hour as determined from the sleep diary) in eachdosing period according to the study randomization schedule. For allsubjects in the study in each study period, urinalysis with microscopywas performed after the first dose and the results assessed before thesecond dose of study drug was administered. The C-SSRS was alsoadministered upon check-in on Days 1 and 8 and before discharge on Days3 and 10.

Following the evening-time dosing with study drug, subjects underwenteight hours of continuous PSG recording. Next-day residual effects wereassessed by the DSST, KSS, POMS-standard, and the PVT, all of which werecollected in the order specified, starting at approximately 30 minutesafter “lights-on.” All tests (except the POMS-standard, which wasadministered once at lights-on) were administered in the clinical unit,beginning 30 minutes after lights-on and every 90 minutes thereafter forapproximately 16 hours post-lights-off, following PSG recording. Eachsubject also completed a sleep questionnaire once after lights-on sothat subjective impressions could be assessed about the quality andquantity of their sleep. Before the second night dosing in each dosingperiod, subjects were evaluated for any residual sleepiness. Forsubjects who exhibited continued sedation, the second night dosing waswithheld. Subjects remained in the clinic until residual symptoms wereminimized.

Prior to discharge from Dosing Period 1 (Day 3), subjects had aurinalysis with microscopy, chemistry and hematology collected.

A 24-hour urine collection was initiated immediately post-first dose ineach dosing period. Blood was collected after the second dose in eachperiod to determine the concentration of drug and, possibly, itsmetabolites.

(3) A follow-up period (Days 16 to 19) included a telephone callcompleted 7 to 10 days after the last dose of the study drug to monitoradverse effects and use of concomitant medication/therapy since theprevious visit.

6.2 Example 2: Statistical Methods

In general, categorical variables were summarized by the count (“n”) andpercentage of subjects. Continuous variables were summarized by thenumber of non-missing observations (“n”), mean, standard deviation(“SD”), standard error of the mean, median, and minimum and maximumvalues.

The full-analysis population (“FAP”) was the group of subjects who wererandomized and received one dose of the study drug. Exposure to studydrug was presented for each treatment group. The analysis population forefficacy was the FAP.

Efficacy endpoints—The primary efficacy variable was the effects ofCompound (1D) on SE as measured by PSG. For the purposes of summary andanalysis, the mean SE obtained from PSG was used per subject pertreatment. It was derived by taking the mean of SE for Days 1 and 2 pertreatment period or baseline. The two PSG nights in each treatmentperiod were averaged before comparison. When data from only one of thesedays were available, the available data were taken as the measurementfor that period. The baseline, post-baseline, and change of baseline ofSE were summarized by treatment group by using descriptive statistics.The statistical analysis to compare Compound (1D) versus placebo wasperformed by using a mixed model approach that included period,sequence, and treatment as fixed effects, subject within the sequence asrandom effect, and the baseline measurement of SE as a covariate. The2-sided significance level of 0.05 was used for comparison.

Subjects underwent eight hours of PSG recording, and PSGs were collectedand scored by a central reader. Sleep stages were scored following AASMstandard criteria based on 30-second epochs. Polysomnography parameters,including LPS, REM latency, NAW, TST, WASO, and total minutes of Stagesof N1, N2, N3, and REM were compared between the two treatment periods(Compound (1D) versus placebo). Sleep quality and depth of sleep asmeasured by the post-sleep questionnaire were also compared between thetwo treatment periods (Compound (1D) versus placebo).

The baseline, post-baseline, and change from baseline of WASO weresummarized by treatment group by using descriptive statistics. Theanalysis was performed by using a mixed model approach that includedperiod, sequence, and treatment as fixed effects, subject withinsequence as random effect, and the baseline measurement of WASO ascovariate.

Other secondary variables (LPS; TST; total minutes of Stages of N1, N2,N3, and REM; REM latency; NAW as measured by PSG; and sleep quality anddepth of sleep as measured by the post-sleep questionnaire) weresummarized and analyzed as detailed above for the WASO parameter. Thenext-day residual effects parameters, measured by DSST, KSS,POMS-standard, and PVT, were summarized using descriptive statistics.

Missing data handling—For analyses of change from baseline, baseline wasgenerally defined as the pre-dose assessment on Day −6 or earlier asscheduled. If this value was unavailable, the last non-missing valuebefore dosing was used. Otherwise, missing observations were treated asmissing at random, and no data imputation was performed.

Sample size determination—Rationale to support the sample sizeestimation was derived from results of a PSG study published by Scharfet al. (“A multicenter, placebo-controlled study evaluating zolpidem inthe treatment of chronic insomnia,” J. Clin. Psychiatry 55(5):192-199(1994)). Mean percent SE for the low dose of 10 mg zolpidem group, asmeasured by PSG in chronic insomniacs, was typically 7% higher than forthe placebo group, representing an increase of 25 to 40 minutes.Moreover, in the publication of Roth et al. (“A 2-night, 3-period,crossover study of ramelteon's efficacy and safety in older adults withchronic insomnia,” Curr. Med. Res. Opin. 23(5):1005-1014 (2007)), the SDof the differences between active and placebo was approximately 9. Inthe absence of pre-existing information on the ORL-1 active dose for SE,in this study a SD of 10 was used as a conservative estimate ofdispersion.

Safety—Subjects' adverse effects (“AEs”) were categorized into preferredterms and associated system organ class (“SOC”) using the MedicalDictionary for Regulatory Activities (“MedDRA”, version 16.1).Treatment-emergent AEs (“TEAEs”) were defined as AEs that start after orincrease in severity after the first dose of study drug. An AE occurringafter the first dose of study drug was considered to be a TEAE and wasassigned to the most recent treatment administered. Treatment-emergentAEs were summarized by presenting the incidence of AEs for eachtreatment group by the MedDRA preferred term, nested within SOC for thesafety population.

6.3 Example 3: Sleep Efficiency Results

The full SE data set obtained for each of the periods described inExamples 1 and 2 above is provided above the double line in Table 1below; a compilation and analysis for screening and treatment appearsbelow the double line in Table 1.

TABLE 1 Summary of Sleep Efficiency (“SE”) During 8 Hours Post-Dose perNight (Full Analysis Population) Placebo Compound (1D) Overall (N = 21)(N = 19) (N = 22) Screening Period (Baseline) Night 1 n 22 Mean (SD)71.67 (13.899) Median 77.60 Minimum, Maximum   32.5, 87.7 ScreeningPeriod (Baseline) Night 2 n 22 Mean (SD) 78.84 (7.316) Median 79.12Minimum, Maximum   63.0, 90.2 Treatment Period 1 Night 1 n 11 11 22 Mean(SD) 80.12 (10.828) 88.33 (6.777) 84.23 (9.786) Median 81.25 87.40 86.30Minimum, Maximum   60.2, 92.2 74.7, 97.7   60.2, 97.7 Treatment Period 1Night 2 n 10 11 21 Mean (SD) 84.45 (7.020) 91.63 (4.078) 88.21 (6.633)Median 86.41 92.29 91.25 Minimum, Maximum   70.2, 93.4 80.7, 95.6  70.2, 95.6 Treatment Period 2 Night 1 n 10  8 18 Mean (SD) 75.58(14.615) 93.56 (2.488) 83.57 (14.147) Median 77.08 94.38 88.37 Minimum,Maximum   39.7, 90.0 88.3, 95.5   39.7, 95.5 Treatment Period 2 Night 2n 10  8 18 Mean (SD) 80.73 (5.727) 93.23 (1.790) 86.28 (7.716) Median81.25 93.80 87.24 Minimum, Maximum   67.1, 88.9 90.8, 95.7   87.1, 95.7Screening Period Mean (Baseline) n 22 Mean (SD) 75.258 (8.5767) Median76.745 Minimum, Maximum   47.76, 87.24 Treatment Period Mean n 21 19 22Mean (SD) 79.751 (9.5037) 91.419 (3.8701) 85.294 (9.3835) LSM (STDE)79.74 (1.492) 91.53 (1.588) N/A Median 83.178 92.396 86.432 Minimum,Maximum   53.39, 91.72 81.72, 96.67   53.39, 96.67 Change from Baselinen 21 19 22 Mean (SD)  4.488 (9.0922) 15.986 (7.9225)  9.950 (10.2554)LSM (STDE)  4.40 (1.492) 16.18 (1.588) N/A Median  5.469 15.365  9.427Minimum, Maximum −11.46, 26.93  2.60, 41.25 −11.46, 41.25 StatisticalTesting Drug Effect Difference (LSM (STDE)) 11.79 (2.180) 95% ConfidenceInterval (7.17, 16.41) P-value  0.0000581

Table 2 below summarizes the results of the SE determinations; the barchart in FIG. 1 provides a graphical representation of SE wherein the“average” bar represents the average of assessment on Night 1 and Night2 of each study period.

TABLE 2 Results of SE Determinations Placebo Compound (1D) SleepEfficiency (SE, %) (N = 21) (N = 19) Mean Baseline (SD) 75.3 (8.8) 75.4(8.7) Treatment Period Mean (SD) 79.8 (9.5) 91.4 (3.9) LSM Change fromBaseline  4.4 (1.5) 16.2 (1.6) (STDE) LSM Effect Difference (STDE) —11.8 (2.2) P-value — <0.001

As is evident from the data in FIG. 1 and Table 2, Sleep Efficiency, theprimary efficacy variable, was significantly increased in the treatmentgroup, exhibiting a LSM increase effect of 11.8 minutes.

6.4 Example 4: Latency to Persistent Sleep Results

The full LPS data set obtained for each of the periods described inExamples 1 and 2 above is provided above the double line in Table 3below; a compilation and analysis for screening and treatment appearsbelow the double line in Table 3.

TABLE 3 Summary of Latency to Persistent Sleep (“LPS”) in Minutes perNight (Full Analysis Population) Placebo Compound (1D) Overall (N = 21)(N = 19) (N = 22) Screening Period (Baseline) Night 1 n   22 Mean (SD)  52.43 (42.691) Median   41.00 Minimum, Maximum    15.0, 218.5Screening Period (Baseline) Night 2 n   22 Mean (SD)   49.18 (32.649)Median   38.75 Minimum, Maximum   18.0, 142.5 Treatment Period 1 Night 1n   11   11   22 Mean (SD)   36.00 (31.470)   25.68 (15.691)   30.84(24.834) Median   26.50   24.50   25.00 Minimum, Maximum    8.0, 113.0   6.0, 58.0    6.0, 113.0 Treatment Period 1 Night 2 n   10   11   21Mean (SD)   23.75 (15.203)   20.73 (29.755)   22.17 (23.433) Median  18.50   15.00   15.00 Minimum, Maximum    0.0, 47.0    0.0, 105.0   0.0, 105.0 Treatment Period 2 Night 1 n   10    8   18 Mean (SD)  44.95 (37.753)   12.75 (14.425)   30.64 (33.336) Median   28.00   9.00   16.75 Minimum, Maximum    11.0, 119.5    0.0, 46.0    0.0,119.5 Treatment Period 2 Night 2 n   10    8   18 Mean (SD)   38.50(23.287)   12.50 (9.350)   26.94 (22.357) Median   33.00   11.50   20.00Minimum, Maximum    5.5, 70.0    0.5, 29.5    0.5, 70.0 Screening PeriodMean (Baseline) n   22 Mean (SD)   50.807 (27.4393) Median   41.875Minimum, Maximum    20.75, 125.25 Treatment Period Mean n   21   19   22Mean (SD)   35.488 (22.6018)   18.750 (15.6310)   27.538 (21.4775) LSM(STDE)   35.58 (4.305)   18.14 (4.579) N/A Median   28.500   15.000  21.125 Minimum, Maximum    8.25, 78.25    2.00, 70.25    2.00, 78.25Change from Baseline n   21   19   22 Mean (SD) −16.610 (34.7399)−29.918 (23.3435) −22.931 (30.2606) LSM (STDE) −14.89 (4.306) −32.33(4.580) N/A Median −17.500 −27.250 −23.025 Minimum, Maximum −102.75,49.25 −87.75, 8.75 −102.75, 49.25 Statistical Testing Drug EffectDifference (LSM (STDE)) −17.44 (6.292) 95% Confidence Interval (−30.77,−4.10) P-value    0.0136

Table 4 below summarizes the results of the LPS determinations; the barchart in FIG. 2 provides a graphical representation of LPS wherein the“average” bar represents the average of assessment on Night 1 and Night2 of each study period.

TABLE 4 Results of LPS Determinations Latency to Persistent PlaceboCompound (1D) Sleep (LPS, min.) (N = 21) (N = 19) Mean Baseline (SD)  52.1 (27.4)   48.7 (23.0) Treatment Period Mean (SD)   35.5 (22.6)  18.8 (15.6)) LSM Change from Baseline −14.9 (4.3)  −32.3 (4.6) (STDE)LSM Effect Difference ( STDE) — −17.4 (6.3) P-value —    0.0136

As is evident from the data in FIG. 2 and Table 4, Latency to PersistentSleep, a secondary efficacy variable, was significantly reduced in thetreatment group, exhibiting a LSM decrease effect of 17.4 minutes.

6.5 Example 5: Wake after Sleep Onset Results

The full WASO data set obtained for each of the periods described inExamples 1 and 2 above is provided above the double line in Table 5below; a compilation and analysis for screening and treatment appearsbelow the double line in Table 5.

TABLE 5 Summary of Wake After Sleep Onset (“WASO”) in Minutes per Night(Full Analysis Population) Placebo Compound (1D) Overall (N = 21) (N =19) (N = 22) Screening Period (Baseline) Night 1 n   22 Mean (SD)  91.59 (65.222) Median   67.25 Minimum, Maximum    28.5, 306.0Screening Period (Baseline) Night 2 n   22 Mean (SD)   59.50 (32.539)Median   52.00 Minimum, Maximum    19.0, 161.0 Treatment Period 1 Night1 n   11   11   22 Mean (SD)   59.27 (27.021)   35.95 (29.815)   47.61(30.222) Median   59.00   29.50   41.50 Minimum, Maximum   18.0, 104.5   7.5, 111.5    7.5, 111.5 Treatment Period 1 Night 2 n   10   11   21Mean (SD)   55.75 (28.412)   25.68 (12.515)   40.00 (26.045) Median  50.75   25.50   30.00 Minimum, Maximum   23.5, 106.5     4.0, 52.0   4.0, 106.5 Treatment Period 2 Night 1 n   10    8   18 Mean (SD)  79.70 (58.140)   15.63 (4.299)   51.22 (53.577) Median   55.75   15.75  31.00 Minimum, Maximum   30.0, 206.5     9.5, 22.5    9.5, 206.5Treatment Period 2 Night 2 n   10    8   18 Mean (SD)   58.20 (39.398)  23.44 (8.946)   42.75 (34.215) Median   48.25   22.75   29.75 Minimum,Maximum   16.0, 140.5    12.5, 38.5    12.5, 140.5 Screening Period Mean(Baseline) n   22 Mean (SD)   75.545 (44.3455) Median   67.750 Minimum,Maximum    26.75, 233.50 Treatment Period Mean n   21   19   22 Mean(SD)   63.262 (36.0320)   26.066 (16.2181)   45.594 (33.7796) LSM (STDE)  53.74 (5.633)   25.28 (5.990) N/A Median   56.750   22.250   32.000Minimum, Maximum   22.75, 173.50    11.00, 51.75    11.00, 173.50 Changefrom Baseline n   21   19   22 Mean (SD) −10.898 (36.4550) −50.545(42.1544) −29.730 (43.6316) LSM (STDE) −11.58 (5.633) −50.04 (5.990) N/AMedian −14.000 −47.250 −24.375 Minimum, Maximum −89.50, 54.50 −185.50,29.50 −185.50, 54.50 Statistical Testing Drug Effect Difference (LSM(STDE)) −38.46 (8.222) 95% Confidence Interval (−55.89, −21.03) P-value   0.0003

Table 6 below summarizes the results of the WASO determinations; the barchart in FIG. 3 provides a graphical representation of WASO wherein the“average” bar represents the average of assessment on Night 1 and Night2 of each study period.

TABLE 6 Results of WASO Determinations Wake After Sleep Onset PlaceboCompound (1D) (WASO, min.) (N = 21) (N = 19) Mean Baseline (SD)   74.2(44.9)   76.6. (43.2) Treatment Period Mean (SD)   63.3 (36.0)   26.1(16.2) LSM Change from Baseline −11.6 (5.6)  −50.0 (6.0) (STDE) LSMEffect Difference (STDE) — −38.5 (8.2) P-value —    0.0003

As is evident from the data in FIG. 3 and Table 6, Wake After SleepOnset, a secondary efficacy variable, was significantly reduced in thetreatment group, exhibiting a LSM decrease effect of 38.5 minutes.

6.6 Example 6: Total Sleep Time Results

The full TST data set obtained for each of the periods described inExamples 1 and 2 above is provided above the double line in Table 7below; a compilation and analysis for screening and treatment appearsbelow the double line in Table 7.

TABLE 7 Summary of Total Sleep Time (“TST”) in Minutes per Night (FullAnalysis Population) Placebo Compound (1D) Overall (N = 21) (N = 19) (N= 22) Screening Period (Baseline) Night 1 n  22 Mean (SD) 344.02(66.717) Median 372.50 Minimum, Maximum   156.0, 421.0 Screening Period(Baseline) Night 2 n  22 Mean (SD) 378.45 (35.119) Median 379.75Minimum, Maximum   302.5, 433.0 Treatment Period 1 Night 1 n  11  11  22Mean (SD) 369.73 (90.385) 424.00 (32.530) 396.86 (71.872) Median 390.00419.50 414.25 Minimum, Maximum   128.0, 442.5 358.5, 469.0   128.0,469.00 Treatment Period 1 Night 2 n  10  11  21 Mean (SD) 405.35(33.696) 439.82 (19.572) 423.40 (31.838) Median 414.75 443.00 438.00Minimum, Maximum   337.0, 448.5 387.5, 459.0   337.0, 459.0 TreatmentPeriod 2 Night 1 n  10  8  18 Mean (SD) 362.80 (70.150) 416.88 (101.558)386.83 (87.274) Median 370.00 453.00 418.75 Minimum, Maximum   190.5,432.0 166.0, 458.5   166.0, 458.5 Treatment Period 2 Night 2 n  10  8 18 Mean (SD) 387.50 (27.488) 447.50 (8.594) 414.17 (37.035) Median390.00 450.25 418.75 Minimum, Maximum   322.0, 426.5 436.0, 459.5  322.0, 459.5 Screening Period Mean (Baseline) n  22 Mean (SD) 361.239(41.1681) Median 368.375 Minimum, Maximum   229.25, 418.75 TreatmentPeriod Mean n  21  19  22 Mean (SD) 375.036 (69.6000) 432.026 (35.1088)402.106(62.3202) LSM (STDE) 375.40 (12.094) 431.09 (12.869) N/A Median399.250 443.500 414.125 Minimum, Maximum   128.00, 440.25 309.00, 464.00  128.00, 464.00 Change from Baseline n  21  19  22 Mean (SD)  13.776(66.2278)  69.955 (49.2950)  40.461 (64.6379) LSM (STDE)  13.75 (12.095) 69.44 (12.870) N/A Median  26.250  73.750 44.125 Minimum, Maximum−216.00, 129.25 −59.80, 198.00 −216.00, 198.00 Statistical Testing DrugEffect Difference (LSM (STDE))  56.69 (17.665) 95% Confidence Interval(18.04, 93.34) P-value  0.0066

Table 8 below summarizes the results of the TST determinations; the barchart in FIG. 4 provides a graphical representation of TST wherein the“average” bar represents the average of assessment on Night 1 and Night2 of each study period.

TABLE 8 Results of TST Determinations Total Sleep Time Placebo Compound(1D) (TST, min.) (N = 21) (N = 19) Mean Baseline (SD) 361.3 (42.2) 362.1(41.7) Treatment Period Mean (SD) 375.0 (69.6) 432.0 (35.1) LSM Changefrom Baseline  13.8 (12.1)  69.4 (12.9) (STDE) LSM Effect Difference(STDE) —  56.7 (17.7) P-value —  0.0066

As is evident from the data in FIG. 4 and Table 8, Total Sleep Time, asecondary efficacy variable, was significantly increased in thetreatment group, exhibiting a TST increase effect of nearly an hour:56.7 minutes.

6.7 Example 7: In Vitro Assay of the Solubility of Compounds (1F), 405K,and W-212393

Aqueous solubility of compounds is often a desirable feature. Forexample, aqueous solubility of a compound permits that compound to bemore easily formulated into a variety of dosage forms that may beadministered to an animal. When a compound is not fully soluble in theblood, it may precipitate from the blood, and the animal's exposure tothe drug will accordingly not correspond to the administered dose.Aqueous solubility increases the likelihood that a compound will notprecipitate in an animal's blood, and increases the ability to predictexposure at the target sight of the compound.

A first procedure by which the solubility was determined was as follows.The compound was dissolved in dimethyl sulfoxide to provide a 10 mM testcompound in DMSO stock solution. To each of 32 wells, containing aminiature magnetic stirrer, of a 96-well v-bottom plate (0.5 mL/well)was added 400 μL of Japanese Pharmacopoeia Disintegration Test solutionnumber 2 (“JP2”) having a pH of about 6.8. 4 μL of test compound stocksolution was added to each well, the plate placed on a plate stirrer,and the solutions were allowed to mix for about 16 hours at atemperature of about 25° C. The solutions from all wells were thentransferred to the corresponding wells of a new plate having nostirrers. The new plate was centrifuged at a temperature of about 25° C.for 10 minutes at 1,200 relative centrifugal force.

A sample plate was prepared as follows. A 50 μL portion of thecompound/JP2 supernatant from each new plate well was transferred to acorresponding well of a shallow-96-well, v-bottom LC-MS sample plate.Another 150 μL portion of the compound/JP2 supernatant from each newplate well was transferred to a corresponding well of a polycarbonatefilter plate (Millipore MSSLBPC10), filtered using a Millipore vacuummanifold, and the filtrate collected in a shallow-well receiver plate.50 μL of filtrate from each receiver plate well was transferred to acorresponding well of the LC-MS sample plate. To each sample plate wellwas added 50 μL of HPLC grade methanol, the solutions were mixed, andthe wells were sealed with septa.

A LC-MS reference plate was also prepared with multiple wells containing1 μL of a solution of 10 mM of each compound in DMSO serially dilutedwith 500 μL of methanol then 500 μL of water.

10 μL of a compound solution from each sample plate well was injectedinto the LC-MS apparatus having a uv-detector and the peak area of peaksat 282 nm (30 nm width), 244 nm (20 nm width), and 223 nm (6 nm width)was obtained. 5 μL of the reference standard for that test compound wasalso injected and the areas of the same peaks obtained. The MS portionof the apparatus was used to ensure that the correct peak was analyzed.From multiple sample and reference determinations, the averagecompound's solution concentration was calculated for each peakwavelength and then the results at all wavelengths were averaged toprovide the tabulated final solubility result.

A second procedure by which the solubility of each compound wasdetermined was as described above except 50 mM of phosphate buffer witha pH of 6.8 replaced JP2, the centrifugation was omitted and, after thecompletion of stirring, the entire contents of each well was filteredthen diluted with twice the volume of methanol. Analysis was by HPLCwith uv detection at the three peaks described above. From the peakareas determined, the average compound's solution concentration wascalculated for each peak wavelength and the results at all wavelengthswere averaged. 10 μM test compound reference standards were made intriplicate and the areas determined for each wavelength were averaged.The tested compound solubility was calculated as follows:

$\begin{matrix}{{{Solubility}\mspace{11mu} ({\mu M})} = {2 \times \left( {{{Avg}.\mspace{14mu} {area}}\mspace{14mu} {of}\mspace{14mu} {test}\mspace{14mu} {compound}} \right) \times {\frac{10\mspace{14mu} {\mu M}}{{{Avg}.\mspace{14mu} {area}}\mspace{14mu} {of}\mspace{14mu} {standard}}.}}} & \left( {{Eq}.\mspace{14mu} 1} \right)\end{matrix}$

Table 9 below summarizes the results of the solubility determinationsfor Compound (1F), Compound 405K, and the free base of CompoundW-212393. The results from two separate determinations, by each of theabove-described methods respectively, are presented for Compounds (1F)and 405K.

TABLE 9 Results of Solubility Determinations Compound Compound Compound(1F) 405K W-212393 Solubility >50, 35 8, 5 42 (μM) at pH 6.8

Compound (1F) was highly soluble in aqueous solution. For example, at apH of about 6.8 Compound (1F) had an aqueous solubility of at least 35μM. In contrast, Compound 405K had a relatively low aqueous solubilityat a pH of about 6.8, averaging about 6.5 μM. Its aqueous solubility atthis pH was, at most, about 0.19 of the solubility of Compound (1F)[6.5/35=0.19, 6.5/50=0.13].

6.8 Example 8: In Vitro Assay of Metabolic Stability of Compounds (1F),405K, and W-212393

The comparative in vitro metabolic stabilities of Compounds (1F), 405K,and W-212393 were determined upon exposure to human liver microsomes orrat liver microsomes according to a procedure disclosed in, e.g.,Example 14 of U.S. Pat. No. 9,290,488, which is hereby incorporated byreference in its entirety. Liver microsomes from Crj;CD rats or humanswere incubated with 2 μM of each tested compound; thereafter, thesupernatant was analyzed by HPLC-MS for the concentration of the testedcompound present.

Human liver microsomes, pooled, 20 mg/mL, were obtained from XenoTechLLC (Lexena, KS, cat# H0610). Rat liver microsomes were obtained from8-week-old Crj:CD (SD) male rats. Alternatively and if desired, ratliver microsomes can be obtained commercially from, e.g., XenoTech(Sprague-Dawley rat liver microsomes, pooled, 20 mg/mL, cat# R1000).β-NADPH (β-nicotinamide adenine dinucleotide 2′-phosphate reducedtetrasodium salt hydrate) was obtained from Oriental Yeast Co., Ltd.(Tokyo, Japan).

Each tested compound, present at an initial concentration of 2 μM, wasincubated at 37° C. in the presence of 0.5 mg/mL of either humanmicrosomes or rat microsomes in suspension in 50 mM Tris-HCl buffer (7.4pH), 150 mM KCl, 10 mM MgCl₂, and 1 mM 13-NADPH. Incubation wasinitiated upon the addition of a 100-fold concentrated solution of thetested compound to one of the microsome preparations. Incubation wasterminated by addition of a two-fold volume of a 1/1 mixture ofacetonitrile/methanol after either 0 minutes or 30 minutes of incubationat 37° C. Thereafter, proteins and other macromolecules from themicrosome preparation were removed by centrifugation. All incubationswere conducted in duplicate.

The mean tested compound concentration was determined after 0 minutes or30 minutes of incubation using an HPLC-MS apparatus. The HPLC systemconsisted of a Waters 2795 separations module (Waters Corp., Milford,Mass.) equipped with an inline degasser, temperature controlledauto-sampler, and column oven. The analytical column was a WatersATLANTIS C18 3.5 μm, 2.1 mm×20 mm column. The mass analyzer was a WatersZQ, single quadrupole mass spectrometer equipped with an electrosprayionization source operating in the positive ionization mode andutilizing a stainless steel spray capillary.

A 5 μL volume of the supernatant obtained after each incubation wasinjected into the above-described reverse-phase column maintained at atemperature of about 25° C. and eluted using a solvent gradient (solventA is 0.1% aqueous formic acid, solvent B is acetonitrile). The HPLCelution conditions were as follows: 5% of solvent B (with the balancesolvent A); followed by a linear gradient to 90% of solvent B in 0.1minutes; followed by 90% of solvent B for 2.9 minutes; followed by agradient to 5% of solvent B in 0.1 minutes. The column was thenequilibrated with 5%/95% of solvent B/solvent A for 1.5 minutes beforethe next injection. The flow rate was kept constant at 0.4 mL/min. TheMS was operated in the selected ion recording mode. The capillary energyand cone energy were 1.5-2.5 kV and 20-40 V, respectively.

The percentage of tested compound remaining after 30 minutes ofincubation in the presence of either human liver microsomes or rat livermicrosomes was calculated from the determinations of the mean testedcompound concentrations after 0 minutes and 30 minutes of incubation.

Table 10 below summarizes the results of the metabolic stabilitydeterminations for Compounds (1F), 405K, and W-212393.

TABLE 10 Results of Metabolic Stability Determinations Compound CompoundCompound (1F) 405K W-212393 Human 98.7 95.1 27.3 Metabolic Stability (%)Rat Metabolic 95.3 96.9 58.4 Stability (%)

As can be noted from the results in Table 10, the metabolic stability ofCompound W-212393 upon exposure to either one of the sources of livermicrosomes was significantly below 100% (i.e., the value forunmetabolized compound). For example, the metabolic stability ofCompound W-212393 upon exposure to human liver microsomes, i.e., theamount of the compound remaining after 30 minutes of incubation relativeto the initial amount present after 0 minutes of incubation (expressedas a percentage of the initial amount) was only 27.3%. In contrast, themetabolic stability of Compound (1F) upon exposure to human livermicrosomes was much greater, 98.7%, or about 3.6 times greater(98.7%/27.3%). In another example, the metabolic stability of CompoundW-212393 upon exposure to rat liver microsomes was only 58.4%. Incontrast, the metabolic stability of Compound (1F) upon exposure to ratliver microsomes, 95.3%, was about 1.6 times greater (95.3%/58.4%).Based on these in vitro results, it is believed that Compound (1F) iseffective in resisting metabolism by the liver in vivo and, thus, beingmore available will be more effective in ORL-1 receptor modulation thanCompound W-212393.

6.9 Example 9: In Vivo Assay of the Bioavailability of Compounds(1C)/(1E), 405K, and W-212393

Male Sprague-Dawley [Crl:CD(SD)] rats obtained from Charles RiverLaboratories Japan, Inc. were used in each determination. The rats were8 weeks old on the day of test compound administration. Under isofluraneanesthesia, the rats were first subjected to surgery to insert a cannulatube into the jugular vein at least three days before test compoundadministration. Rats were selected for further study based on thecondition of the blood sampling apparatus and their body weight changeafter surgery.

Each compound tested was administered in a methylcellulose aqueoussolution once orally to 2 rats. Methylcellulose 400 cP (Wako PureChemical Industries, Ltd., Japan) was the methylcellulose used for alladministrations. To make each formulation for oral administration, anappropriate amount of the test compound was weighed into an agate mortarand suspended with 0.5 w/v % methylcellulose aqueous solution vehicle toprovide a suspension with a concentration of 0.2 mg/mL of the compoundundergoing testing.

The rats were dosed orally at 1 mg/kg under non-anesthesia in anon-fasted condition. Blood (0.2 mL/sample) was collected through thejugular cannula using a 1 mL syringe containing anticoagulants (0.89 MEDTA-2K plus 20% heparin) at various time points (0.25, 0.5, 1, 2, 4, 6,8, and 24 hours) after dosing. Replacement fluid—0.2 mL of salinesolution—was administered through the jugular cannula after eachsampling. The blood samples obtained were centrifuged at a temperatureof about 4° C. for 10 minutes at 3,500 rpm to obtain plasma. Thereafter,each plasma sample was transferred into a tube and stored in a freezerfor later workup and analysis.

The supernatants obtained following protein precipitation of the plasmasamples were analyzed by liquid chromatography with tandem massspectrometry detection (“LC-MS-MS”) to determine the concentration oftest compound at each time point. The samples thus analyzed wereprepared without an internal standard. Therefore, the analytical methodmade use of a calibration curve constructed from the analysis of blank(i.e., undosed) plasma spiked with various known quantities of analyteunder identical conditions. From this information, pharmacokineticparameters, in particular bioavailability, were calculated usingWINNONLIN software (Certara, L.P., Princeton, N.J.) based on anon-compartment model.

In connection with Compound (1), multiple determinations were conductedin this example—some with the free base Compound (1C) and some with themono-hydrochloride salt Compound (1E). To indicate this, the designationCompound (1C)/(1E) is used. Table 11 below summarizes the results of thebioavailability determinations for Compounds (1C)/(1E), 405K, andW-212393. The mean bioavailability from multiple determinations isprovided in Table 11. The number in parenthesis following the meanindicates the number of determinations from which the mean was obtained.For Compound (1C)/(1E), bioavailability determination results from whichthe mean was obtained ranged from a low of 25.7% to a high of 58.5%.

TABLE 11 Results of Bioavailability Determinations Compound CompoundCompound (1C)/(1E) 405K W-212393 Average 41.4 (14) 63.7 (2) 2.1 (2)Bioavailability (%)

As can be noted from the results in Table 11, the averagebioavailability was strikingly lower for Compound W-212393 relative toCompound (1C)/(1E). Specifically, the bioavailability of Compound(1C)/(1E) was, on average, 41.4%. In contrast, the averagebioavailability of Compound W-212393 was 2.1%. Thus, the amount ofCompound (1C)/(1E) bioavailable for, inter alia, receptor modulation,was at least about 20 times greater (41.4%/2.1%=19.7). Even for thelowest bioavailability value determined for Compound (1C)/(1E) from all14 experiments, 25.7%, the amount of Compound (1C)/(1E) bioavailable wasstill at least about 12 times greater than for Compound W-212393(25.7%/2.1%=12.2).

6.10 Example 10: In Vitro Assay of Free Unbound Compounds (1F) andW-212393

The extent of in vitro binding of Compound (1F) or W-212393 to rat serumwas determined as an assessment of the availability of free unboundcompound for modulating receptor activity according to a proceduredisclosed in, e.g., Example 15 of U.S. Pat. No. 9,290,488, which ishereby incorporated by reference in its entirety. Serum from ratscontaining a tested compound in one chamber of a dialysis cell wasdialyzed with phosphate buffered saline (“PBS”) in the other chamber;thereafter, the supernatant from each chamber was analyzed for theconcentration of the tested compound present.

0.5 mg/kg of each tested compound was solubilized in 1/1N,N-dimethylacetamide/1,2-propane diol. Control rat serum was obtainedas the supernatant product after coagulation and centrifugation (3000rpm for 10 min. at 4° C.) of whole blood taken via cannula inserted intothe jugular vein of rats (Crl:CD (SD), male, fed). 50 μL of each testedcompound solution was added to 1.2 mL of control rat serum. The finalconcentration of each tested compound in the serum sample was adjustedto 2 μg/mL by adding an appropriate volume of PBS. A cell suitable forequilibrium dialysis was used in the determinations. A SPECTRA/PORdialysis membrane (with molecular mass cutoff of 12,000-14,000 Da,Spectrum Laboratories, Inc., Rancho Dominguez, Calif.) separated thedialysis cell into two chambers. A 500 μL aliquot of the serum samplecontaining a tested compound was applied to one chamber (serum chamber)of the dialysis cell. A 500 μL aliquot of PBS was applied to the otherchamber (PBS chamber) of the dialysis cell. The dialysis study wasconducted in duplicate for each tested compound.

After 24 hours of equilibrium dialysis at 37° C., 30 μL of liquid fromthe serum chamber of the dialysis cell was collected and to this wasadded 270 μL of fresh PBS (this combination was designated Sample “A”).Then, 270 μL of liquid from the PBS chamber of the dialysis cell wascollected and to this was added 30 μL of control rat serum (i.e., ratserum never exposed to any test compound, this combination wasdesignated Sample “B”). A 5-10 fold volume of methanol was added to eachof Samples A and B. Thereafter, each was mixed vigorously with themethanol and then centrifuged (3000 rpm for 10 min at 4° C.). Eachsupernatant was analyzed by LC-MS-MS.

For each tested compound, the mean amount of tested compound present ineach of Samples A and B was determined from the peak areas obtained byLC-MS-MS analysis. Thereafter, the percentage of free unbound testedcompound was calculated from the ratio of the tested compound amountdetermined from Sample B divided by the sum of the tested compoundamounts determined from Sample A and Sample B.

Table 12 below summarizes the results of the free unbound compoundfraction determinations for Compounds (1F) and W-212393 where the“fraction unbound (%)” is the percentage of free compound that is notbound to plasma proteins. The results from multiple determinations areprovided for Compound (1F).

TABLE 12 Results of Free Unbound Compound Fraction DeterminationsCompound Compound (1F) W-212393 Fraction 65-70 <0.1 Unbound (%)

As can be noted from the results in Table 12, the free unbound compoundfraction was strikingly lower for Compound W-212393 relative to Compound(1F). Specifically, the free unbound compound fraction of Compound (1F)was, on average, 67.5%. In contrast, the free unbound compound fractionof Compound W-212393 was less than 0.1%. Thus, the amount of Compound(1F) available for, inter alia, receptor modulation, was on average atleast about 675 times greater than for Compound W-212393 (67.5%/0.1%).

6.11 Example 11: In Vivo Assay of Brain Penetration of Compounds (1C),405K, and W-212393

The in vivo distribution of Compound (1C), 405K, or W-212393 between ratbrain homogenate and rat plasma was determined. In this method, amixture of plasma and brain homogenate comprised a matrix, which wasanalyzed by LC-MS-MS.

0.5 mg/kg of each tested compound was solubilized in 1/1N,N-dimethylacetamide/1,2-propane diol to provide a blend. The blend wasadministered once intravenously to anesthetized rats (Crl, CD(SD), male,fed). At 30 minutes after the dosing, whole blood was taken from theabdominal aorta of each anesthetized rat and the brain was promptlyremoved.

After adding water (3-fold by weight), the brain was prepared as a 25%(w/w) homogenate using a POLYTRON homogenizer (Kinematica, Inc.,Bohemia, N.Y.). To minimize the effects of the matrix on themeasurement, to the brain homogenate sample was then added theequivalent volume of control (i.e., undosed) rat plasma obtained usingthe centrifugation conditions below.

A dosed-rat plasma sample was collected by centrifugation (3,500 rpm for10 min. at 4° C.) of the whole blood. To again minimize the effects ofthe matrix on the measurement, to the plasma sample was added theequivalent volume of a control brain homogenate, prepared as describedabove but with brain extract from intact control (i.e., undosed) rats.

A 5-10 fold volume of methanol was added to the brain homogenate sampleand to the plasma sample prepared above. After vigorous mixing thesupernatants obtained from each by centrifugation were analyzed byLC-MS-MS. The peak areas of the test compound in each brain homogenatesample and plasma sample were measured. For each compound tested, themean amount of compound present in each of the brain homogenate sampleand the plasma sample was determined from the peak areas obtained byLC-MS-MS analysis. Thereafter, K_(p) values were calculated from themean peak area of the brain homogenate samples (MPA_(brain)) and themean peak area of the plasma samples (MPA_(plasma)) as follows:

$\begin{matrix}{K_{p} = {\frac{4 \times {MPA}_{brain}}{{MPA}_{plasma}}.}} & \left( {{Eq}.\mspace{14mu} 2} \right)\end{matrix}$

Table 13 below summarizes the results of the brain penetrationdeterminations for Compounds (1C), 405K, and W-212393. The results fromtwo separate groups of determinations are provided for Compound (1C).

TABLE 13 Results of Brain Penetration Determinations Compound CompoundCompound (1C) 405K W-212393 K_(p)‡ 0.025, 0.040 0.00 0.5

As can be noted from the results in Table 13, the brain penetration ofCompound W-212393 was strikingly higher relative to Compound (1C).Specifically, the brain penetration of Compound W-212393 was 0.5. Incontrast, the brain penetration of Compound (1C) was, on average, 0.033.Thus, the amount of brain penetration of Compound W-212393 was at leastabout 15 times greater (0.5/0.033=15.2) than the brain penetration ofCompound (1C). Even at the maximum brain penetration value determinedfor Compound (1C), 0.040, the amount of brain penetration of CompoundW-212393 was at least about 13 times greater (0.5/0.040=12.5) than thebrain penetration of Compound (1C).

6.12 Example 12: In Vitro Assay of Protein Binding of Compounds (1F),405K, and W-212393

The extent of in vitro binding of Compound (1F), 405K, or W-212393 torat plasma was determined as an assessment of the protein binding ofeach compound, i.e., compound unavailable for modulating receptoractivity. Plasma from rats containing a tested compound in one chamberof a dialysis cell was dialyzed with PBS in the other chamber;thereafter, the supernatant from each chamber was analyzed for theconcentration of the tested compound present.

A cell suitable for equilibrium dialysis was used in the determinations.The dialysis membrane described in Example 10 (with molecular masscutoff of 12,000-14,000 Da) separated the dialysis cell into twochambers. The membrane was soaked with purified water and PBS beforebeing placed into the dialysis cell.

4 μL of an iv formulation of each tested compound was added to 996 μL ofrat plasma, the latter obtained using syringe containing heparin andEDTA by the procedure described in Example 10, to provide a plasmasample with a tested compound concentration of 2 μg/mL. 450 μL of theplasma sample was applied to one chamber (plasma chamber) of thedialysis cell. A 450 μL aliquot of PBS was applied to the other chamber(PBS chamber) of the dialysis cell. The dialysis study was conducted induplicate for each tested compound.

After 24 hours of equilibrium dialysis at 37° C., 30 μL of liquid fromthe plasma chamber of the dialysis cell was collected and to this wasadded 270 μL of fresh PBS (this combination was designated Sample “1”).Then, 270 μL of liquid from the PBS chamber of the dialysis cell wascollected and to this was added 30 μL of control rat plasma (i.e., ratplasma never exposed to any test compound, this combination wasdesignated Sample “2”). Thereafter, each sample was mixed well andstored in a freezer until the next analysis step.

After the protein precipitated in the freezer, each supernatant thuslyobtained was analyzed by LC-MS-MS for unbound test compound. For eachtested compound, the mean amount of tested compound present in each ofSamples 1 and 2 was determined from the peak areas obtained by LC-MS-MSanalysis. Thereafter, the percentage of rat protein-bound (“RPB”) testedcompound was calculated as follows:

$\begin{matrix}{{RPB} = {\left\lbrack {1 - \frac{\left( {10/9} \right) \times {Area}_{{Sample}\mspace{14mu} 2}}{10 \times {Area}_{{Sample}\mspace{14mu} 1}}} \right\rbrack \times 100}} & \left( {{Eq}.\mspace{14mu} 3} \right)\end{matrix}$

Table 14 below summarizes the results of the rat protein bindingdeterminations for Compounds (1F), 405K, and W-212393. The results frommultiple determinations are provided for Compound (1F).

TABLE 14 Results of Protein Binding Determinations Compound CompoundCompound (1F) 405K W-212393 Rat Protein 50.9, 53.0 85.7 N/A Binding (%)

As can be noted from the results in Table 14, the amount of rat proteinbound compound was lower for Compound (1F) relative to Compound 405K.Specifically, the bound compound fraction of Compound (1F) was, onaverage, 52%. In contrast, the bound compound fraction of Compound 405Kwas about 86%. Compound W-212393 proved to be unstable in plasma;because it degraded during the course of the determination, presence ofthe starting molecular structure could not be determined in thesupernatant.

6.13 Example 13: In Vivo Functional Observational Battery of Compounds(1D), 405, and W-212393

Compound (1D) was administered in a 0.5 w/v % methylcellulose aqueoussolution once orally to 6 rats/group at dose levels of 0 (vehiclecontrol), 60, 300, and 600 mg/kg to evaluate the effects on the CNS byusing a functional observational battery (“FOB”). The FOB was conductedpre-dosing and up to 24 hours post-dosing. Control animals (6 rats)received a 0.5 w/v % methylcellulose aqueous solution vehicle (hereafter“0.5% MC”) in a similar manner. Methylcellulose 400 cP (Wako PureChemical Industries, Ltd., Japan) was the methylcellulose used for alladministrations. Analysis and verification of the concentration andhomogeneity of the test substance in the vehicle was conducted bymethods known to those in the art. Measured test substanceconcentrations were 100.7-102.0% of the nominal concentrations with arelative standard deviation of 1.0% or 2.0%.

Male Crl:CD(SD) rats, 4 weeks old upon receipt, were obtained fromCharles River Laboratories Japan, Inc. They were acclimated to a 12-hourlight-dark cycle at a temperature of 22.1-23.6° C. for a 2 weekperiod—from receipt until 1 day prior to dosing. Drinking water wasprovided ad libitum while the rats were caged. The animals were allowedfree access to food except prior to dosing, when they were fasted for atleast 16 hours from the previous evening. On the day of dosing, food wasprovided 8 hours post-dosing.

The body temperature of the rats exhibiting no abnormalities in physicalcondition or body weights during the acclimation period was measuredtwice at an interval of 30-60 minutes. Six week old rats weighing178-220 g and with individual mean body temperature ranging between 37°C. and 39° C. and with less variation between the two values werepreferentially selected for the study. The selected rats were randomlydistributed into groups of 6 using a stratified randomization procedurebased on body temperature.

A single administration was made with the dosing volume for each ratcalculated based upon its body weight on the day of dosing (prior todosing). The dosing formulations were drawn into the appropriate size ofsterile, disposable polypropylene syringes while being stirredthoroughly with a stirrer and then administered to the rats via oralgavage using gastric intubation tubes. Observation of the rats wasconducted by 3 observers, all of whom were outside of the animal roomduring dosing, at a plurality of the following time points: pre-dosingand at 0.5 (optionally), 1, 2, 4, 6 (optionally), 8 (optionally), and 24(optionally) hours post-dosing. Observer 1 recorded home cage andhand-held observations and body temperature measurements. Observer 2recorded open-field observations. Observer 3 recorded observations forsensorimotor reflexes. Table 15 provides the specific observationparameters that were noted by the observers.

TABLE 15 Specific Observation Parameters Home cage Posture/position,vocalization, piloerection, observations tremors, convulsions,respiration, feces and urine Hand-held Ease of handling and removal fromthe cage, observations body temperature (rectal), muscle twitching,muscle tone, skin, pupil size, lacrimation, exophthalmos and salivationOpen field Stereotypy, abnormal behavior, locomotor activity,observations palpebral closure and gait Sensorimotor reflex Catalepsy,knuckling, pupillary reflex, palpebral observations reflex, pinnareflex, visual placing response, auditory response, pain response,wheelbarrowing, hopping, aerial righting reflex, hindlimb landingfoot-splay and forelimb grip strength

The mean group values and SDs were calculated for numerical data (bodytemperature, pupil size, hindlimb landing foot-splay, grip strength) andthe data were analyzed for homogeneity of variance using Bartlett's test(5% level of significance). When the variance was homogeneous betweenthe groups, Dunnett's test was conducted between the control and testsubstance groups. When the variance was heterogeneous based onBartlett's test, a mean rank test of the Dunnett type was conducted.Differences from the control group were evaluated at the two-tailed 5%level of significance and presented as p<0.05 or p<0.01. Differencesfrom the pre-dosing values were calculated for the body temperature andpupil size at the scheduled time points and presented as the mean valuesand SDs. Statistical analysis was not conducted on these values.

No statistically significant differences were noted in the bodytemperature, pupil size, hindlimb landing foot-splay, or forelimb gripstrength between the control and any Compound (1D) treated group.Decreased locomotor activity was observed in 1 rat each in the 300 and600 mg/kg groups at 4 or 8 hours post-dosing; however, this finding atthese time points was considered not to be treatment-related because itwas also observed in 1 or 2 control rats between 4 and 8 hourspost-dosing. In summary, no Compound (1D) treatment-related changes werenoted in home cage, hand-held, open field, or sensorimotor reflexobservation items at any of the time points after up to 600 mg/kg oraldosing with Compound (1D).

In conclusion, because Compound (1D) had no effects on the generalphysical condition or behavior of rats at up to 600 mg/kg, itsno-observed-adverse-effect-level (“NOAEL”) was 600 mg/kg in this study.

The observers noted the adverse effects in Table 16 below upon theadministration of Compound 405 according to the procedures describedabove.

TABLE 16 Adverse Effects Observed upon Administration of Compound 405Test Dose Parameter Time after Administration (hours) Substance (mg/kg)Observed 1 2 4 6 8 24 Vehicle 0 Behavior N N N N N N Compound 10Increased 1 of 6 N N N N N 405 touch response 30 Jumping N N N 1 of 6 NN Biting N N N 3 of 6 N N behavior 100 Biting N N N 1 of 6 1 of 6 Nbehavior 300 Jumping N N N 1 of 6 2 of 6 N Biting N N N 2 of 6 1 of 6 Nbehavior N = Normal or no abnormalities observed Numerical value =Number of rats with each parameter per total number of rats observed

At 10 mg/kg, increased touch response was observed in only 1 of the 6rats dosed. Moreover, because it was a mild and transient effect thiswas likely of only minor physiological significance. However, moresevere FOB parameter abnormalities were evident at higher doses: bitingbehavior at 30, 100, and 300 mg/kg and jumping at 30 and 300 mg/kg. Inlight of these observed FOB abnormalities, it was concluded that theNOAEL for Compound 405 was 10 mg/kg in this study.

The observers noted the adverse effects in Table 17 below upon theadministration of Compound W-212393 also according to the proceduresdescribed above.

TABLE 17 Adverse Effects Observed upon Administration of CompoundW-212393 Time after Administration Test Dose Parameter (hours) Substance(mg/kg) Observed 0.5 1 2 4 6 Vehicle 0 Behavior N N N N N Compound 1Behavior N N N N N W-212393 3 Hvpoactivity N 6 of 6 N N N Jumping N 3 of6 2 of 6 N N Biting behavior N 1 of 6 N N N 300 Jumping 2 of 6 N N N NBiting behavior 3 of 6 N N N N Abdominal 6 of 6 6 of 6 6 of 6 6 of 6 6of 6 position/side lying position Respiratory 6 of 6 6 of 6 6 of 6 6 of6 6 of 6 irregularity Decreased 6 of 6 6 of 6 6 of 6 6 of 6 6 of 6muscle tone Loss of 6 of 6 6 of 6 6 of 6 6 of 6 6 of 6 auricularreflex/righting reflex Loss of flexed 6 of 6 6 of 6 6 of 6 6 of 6 6 of 6or extension reflex Loss of pain 6 of 6 6 of 6 6 of 6 6 of 6 6 of 6reaction N = Normal or no abnormalities observed Numerical value =Number of rats with each parameter per total number of rats observed

At the dose of 300 mg/kg of Compound W-212393, severe FOB parameterabnormalities were observed for all rats. Therefore, additionalevaluations were performed at significantly lower doses (1 and 3 mg/kg).Unlike the FOB abnormalities observed at the 3 mg/kg dose, a dose of 1mg/kg of Compound W-212393 had no effect on general behavior orneurobehavioral function. It was concluded that the NOAEL for CompoundW-212393 was 1 mg/kg in this study.

6.14 Example 14: In Vivo Repeated Administration of Compound (1D)Decreased Wakefulness, Increased NREM Sleep

Compound (1D) was administered in a 0.5 w/v % methylcellulose aqueoussolution once daily orally to rats at a dose level of 30 mg/kg for 7days followed by cessation of administration on the 8^(th) day and itseffects on brain waves (via EEG) and limb movements (via EMG) evaluated.Control animals received 0.5% MC in a similar manner. Themethylcellulose used and analysis and verification of the concentrationand homogeneity of the Compound (1D) solutions administered was asdescribed in Example 13.

Male Crl:CD(SD) rats, 6 weeks old upon receipt, were obtained fromCharles River Laboratories Japan, Inc. At a temperature of 22-24° C.,they were acclimated for at least 5 days to a 12-hour light-dark cyclewith lights on from 6 AM to 6 PM. Drinking water and food were providedad libitum. A telemetry transmitter (TL10M3-F50-EEE, Data SciencesInternational, Inc., Shanghai) which was designed for recording EEG andEMG data from conscious, freely moving rodents was used. In anisoflurane anesthetized rat, a telemetry transmitter was implanted intothe abdominal cavity and a lead line was externalized via the dorsalneck through a subcutaneous tunnel. The rat was placed on a stereotaxicframe and implanted with EEG electrodes according to the brain atlas.The EEG electrodes were placed on the dura matter of the parietal cortex(posterior: 1.8 mm, lateral: ±3.5 mm, from the bregma [the point or areaof the skull where the sagittal and coronal sutures joining the parietaland frontal bones come together]) and the occipital cortex (posterior:5.2 mm, lateral: ±2.0 mm, from the bregma). Two stainless steel wiresfor EMG recording were implanted into dorsal neck muscle of the rat.Each EEG electrode and stainless wire was soldered to the lead line ofthe telemetry transmitter, which was fixed to the skull with quickself-curing acrylic resin (ADFA, Shofu, Inc., Kyoto, Japan). Aftersurgery, each rat was uniquely identified by a serial number marked onits tail. An antibiotic (0.1 mL mycillin sol/rat [Meiji Seika PharmaCo., Ltd., Tokyo]) and an analgesic (0.05 mL buprenorphinehydrochloride/kg [0.2 mg lepetan/mL, Otsuka Pharmaceutical Co., Ltd.,Rockville, Md.]) were administered intramuscularly to the rats for 4days beginning on the day of surgery to prevent infection and palliatepain, respectively. During the recovery period (at least 5 days aftersurgery), the rats were again acclimated as described above in theirrecording cages until the first dosing day.

The first day of a dosing period was designated as Day 1 and dosingcontinued daily on Days 2-7. The rats were 8-10 weeks old on Day 1.Continuous EEG and EMG recording (using DATAQUEST A.R.T. recordingsoftware [Data Sciences International Inc., Tokyo]) was begun 1 hourbefore dosing on Days 1, 4, and 7 of a period and continued for at least24 hours after dosing on Days 1 and 4 and for at least 48 hours afterdosing on Day 7. The sampling frequency for EEG/EMG recording was 500Hz. The cross-over experimental dosing design shown in Table 18 was usedto assess the effects of Compound (1D) on the sleep-wake cycle byEEG/EMG analysis as compared with vehicle treated rats.

TABLE 18 Cross-over Experimental Dosing Design Test Dose GroupDesignation/ Period Substance (mg/kg/day) Number of Rats 14.1 Vehicle 0Group A/4 Compound (1D) 30 Group B/3 14.2 Compound (1D) 30 Group A/4Vehicle 0 Group B/3As described in Example 13, test substance administration was via oralgavage with the dosing volume for each nominally 200 g rat calculatedprior to dosing based upon its exact body weight on the day of dosing.Dosing occurred between 5:30 PM and 5:50 PM. A 7 day wash-out periodduring which there was no administration was used between Periods 14.1and 14.2.

For the purposes of this study, the EEG/EMG data collected wasstructured into 20 second long epochs. Each epoch was scored by analysissoftware (SLEEPSIGN, Kissei Comtec Co., Ltd., Nagano, Japan) as eitherwakefulness, REM sleep, or NREM sleep. The data for all epochs wereexamined manually as a check that the automated scoring was correct. Thepercentage of time spent in each sleep stage was calculated for every 1hour and every 3 hour “time block” by the analysis software. For thepurposes of this study, for either time block the sum of the percentageof time spent in NREM sleep and the percentage of time spent in REMsleep was ascribed to the percentage of time spent sleeping, i.e., tothe sleep portion of the sleep-wake cycle, the percentage of time spentin wakefulness was ascribed to the percentage of time spent notsleeping, i.e., to the wake portion of the sleep-wake cycle, and the sumof the percentages of time spent in NREM sleep, in REM sleep, and inwakefulness equaled 100%. Results from rats that perished during thestudy or were exposed to noise that may have affected the epoch analysiswere excluded. The results obtained were expressed as the meanvalue±STDE. Statistical analyses were performed by SAS analyticssoftware (Release 9.4, SAS Institute Japan, Ltd., Tokyo) using theunpaired student's t-test. The results obtained from the testing areillustrated in FIGS. 5-12. In FIGS. 5-12, the symbol + adjacent to aparticular data point or bar indicates that, for that data point or bar,there is a significant difference from the vehicle by the unpairedstudent's t-test with p<0.05. Also in these figures, the symbol *adjacent to a particular data point or bar indicates that, for that datapoint or bar, there is a significant difference from the vehicle by theunpaired student's t-test with p<0.01.

On Day 1, FIG. 5A illustrates that the percentage of time spent inwakefulness, collected into 1 hour “time blocks”, showed a decreasingtendency at many time points during the about 13 hours after dosing (the“lights-out period”, i.e., from about 0.5 hours to about 13 hours afteradministration of Compound (1D)) compared to the vehicle group and wassignificantly decreased at 4 hours after dosing. Specifically, at 4hours the amount of wakefulness—about 52%—was decreased significantlywhen compared to the about 81% for the vehicle group. Concurrently, FIG.5C demonstrates that the percentage of time spent in desirable NREMsleep showed an increased tendency at many time points during thelights-out period compared to the vehicle group and was significantlyincreased at 4 and 5 hours after dosing. Specifically, at 4 and 5 hoursthe amount of NREM sleep—about 41% and 54%, respectfully—was increasedsignificantly when each is compared to the vehicle group (about 17% and31%, respectively). FIG. 5B shows that the percentage of time spent inless desirable REM sleep was often decreased and decreased significantlyat 7 hours after dosing, i.e., to about 2.5% for 30 mg/kg of Compound(1D) compared to about 7.3% for vehicle. These data provide evidencethat a single 30 mg/kg dose of Compound (1D) on Day 1 had asleep-enhancing effect and induced sleep, in particular, during thelights-out period.

The percentage amounts of Day 1 wakefulness, REM sleep, and NREM sleep,collected into 3 hour “time blocks”, are shown in FIG. 6. Pursuant toFIG. 6A, at 3 to 6 hours after dosing the total amount ofwakefulness—about 47%—was decreased significantly for Compound (1D)administration when compared to the about 65% for the vehicle group.Pursuant to FIG. 6C, the total amount of NREM sleep—about 46%—wasincreased significantly when compared to the about 30% for the vehiclegroup. FIG. 6B illustrates that there were relatively minor effects andno significant effects on the percentage of time spent in REM sleep.These data again provide evidence that a single 30 mg/kg dose ofCompound (1D) on Day 1 had a sleep-enhancing effect and induced sleep,in particular, during the lights-out period.

On Day 4, FIG. 7A illustrates that the percentage of time spent inwakefulness, like in FIG. 5A, again showed a decreasing tendency at manytime points during the lights-out period. Concurrently, FIG. 7Cdemonstrates that the percentage of time spent in NREM sleep showed anincreased tendency at many time points during the Day 4 lights-outperiod compared to the vehicle group and was significantly increased at4 hours after dosing, i.e., about 42% for 30 mg/kg/day of Compound (1D)compared to about 20% for vehicle. FIG. 7B illustrates that there wererelatively minor effects and no significant effects on the percentage oftime spent in REM sleep. From FIG. 8A, it can be noted that at 3 to 6hours after dosing the total amount of wakefulness—about 55%—was againsignificantly decreased while, pursuant to FIG. 8C, the total amount ofNREM sleep was again significantly increased—about 41%—when each iscompared to the vehicle group (about 78% and 19%, respectively). FIG. 8Billustrates that there were relatively minor effects and no significanteffects on the percentage of time spent in REM sleep.

On Day 7, FIG. 9A illustrates that the percentage of time spent inwakefulness showed a decreasing tendency at several time points duringthe lights-out period. Concurrently, FIG. 9C illustrates that thepercentage of time spent in desirable NREM sleep also showed anincreased tendency at several time points during the Day 7 lights-outperiod compared to the vehicle group. FIG. 9B illustrates that therewere relatively minor effects and no significant effects on thepercentage of time spent in REM sleep. From FIG. 10A, it can be notedthat at 3 to 6 hours after dosing the total amount of wakefulness againshowed a decreased tendency while, pursuant to FIG. 10C, the totalamount of NREM sleep again showed an increased tendency when compared tothe vehicle group. FIG. 10B illustrates that there were relatively minoreffects and no significant effects on the percentage of time spent inREM sleep.

The results of Compound (1D) administration over the seven day perioddemonstrate that there was minimal tachyphylaxis, i.e., the diminishingresponse to successive doses of a drug thus rendering it less effectiveover time. It can also be noted from FIGS. 5-10 that, desirably,administration or repeated administration of 30 mg/kg/day of Compound(1D) had no significant deleterious effect on either the percentage oftime spent in wakefulness or the percentage of time spent in NREM sleepduring the time following the lights-out period (the “lights-on period”,i.e., from about 13 hours to about 24 hours after administration). Thus,repeated administration for 7 days did not induce either tolerance orresidual effects in rats at a Compound (1D) dose of 30 mg/kg/day.

Collectively, these data demonstrated that the administration of a 30mg/kg/day dose of Compound (1D) brought about significantsleep-enhancing effects in rats.

The data shown in FIG. 11A for Day 8, which began about 25 hours afterthe Day 7 final administration of Compound (1D), shows that thepercentage of time spent in wakefulness was significantly increased atseveral time points, e.g., at 27, 35, and 46 hours, while, pursuant toFIG. 11C, the percentage of time spent in NREM sleep was significantlydecreased at the same time points during the lights-out and lights-onperiods when compared to vehicle group. These data might possibly beinterpreted to suggest that repeated administration of 30 mg/kg/day ofCompound (1D) for 7 days followed by a 1 day cessation of dosing inducedDay 8 rebound insomnia in rats. However, such an interpretation iscontradicted by other findings. For example, FIG. 11B illustrates thatthe prior administration of Compound (1D) had no effect in Day 8 on thetime spent in REM sleep. Moreover, from FIGS. 12A-12C it can be notedthat the prior administration of Compound (1D) had no significant effectduring most of the lights-out period, having a significant effect onlyduring the initial lights-out period (24-27 hours) in Day 8 on thepercentage amounts of wakefulness and NREM sleep, increasing the formerand decreasing the latter, respectfully.

6.15 Example 15: In Vivo Administration of Compound (1D) as Compared toZolpidem

Compound (1D) was administered in a 0.5 w/v % methylcellulose aqueoussolution once orally to a rat population as described in Example 14 at adose level of either 10 mg/kg or 100 mg/kg and its effects on brainwaves (via EEG) and limb movements (via EMG) evaluated. Control ratsreceived either the 0.5% MC vehicle or a positive control of 10 mg/kg ofthe sleep moderating drug zolpidem (Sigma-Aldrich Japan K.K., Tokyo) in0.5% MC once orally in a similar manner. Note that, pursuant to theMarch 2017 prescribing information for zolpidem tartrate, therecommended human single-administration oral dose is either 5 or 10 mg,i.e., either 0.083 or 0.17 mg/kg, respectively, for a 60 kg human. Anearlier study established that at a far greater 10 mg/kg zolpidem singleoral dose, the induction of NREM sleep in rats was expected. Unlessotherwise disclosed to the contrary in this example, the experimentalprocedures for this example were as described in Example 14.

EEG and EMG recording was begun 1 hour before dosing and continued forat least 24 hours after dosing. The cross-over experimental dosingdesign shown in Table 19 was used to assess the effects of Compound (1D)or zolpidem on the sleep-wake cycle by EEG/EMG analysis as compared withvehicle treated rats.

TABLE 19 Cross-over Experimental Dosing Design Dose Group Designation/Period Test Substance (mg/kg/day) Number of Rats 15.1 Vehicle 0 GroupC/4 Compound (1D) 10 Group D/4 15.2 Compound (1D) 10 Group C/4 Vehicle 0Group D/4 15.3 Vehicle 0 Group E/4 Compound (1D) 100 Group F/3 15.4Compound (1D) 100 Group E/4 Vehicle 0 Group F/3 15.5 Vehicle 0 Group G/3Zolpidem 10 Group H/4 15.6 Zolpidem 10 Group G/3 Vehicle 0 Group H/4A 7 day wash-out period was used between Periods 15.1 and 15.2, Periods15.3 and 15.4, and Periods 15.5 and 15.6. The results obtained from thetesting are illustrated in FIGS. 13-18. In FIGS. 13-18, the symbol +adjacent to a particular data point or bar indicates that, for that datapoint or bar, there is a significant difference from the vehicle by theunpaired student's t-test with p<0.05. Also in these figures, thesymbol * adjacent to a particular data point or bar indicates that, forthat data point or bar, there is a significant difference from thevehicle by the unpaired student's t-test with p<0.01 and the symbol Δadjacent to a particular data point or bar indicates that, for that datapoint or bar, there is a significant difference from the vehicle by theunpaired student's t-test with p<0.001.

At a 10 mg/kg dose of Compound (1D), FIG. 13A illustrates that thepercentage of time spent in wakefulness, collected into 1 hour “timeblocks”, was lower at 2, 5, and 8 hours after dosing during thelights-out period with Compound (1D) relative to the vehicle group.However, wakefulness was significantly increased at 6 hours afterdosing, i.e., during the lights-out period, and at 15 hours afterdosing, i.e., during the lights-on period, when compared to the vehiclegroup. FIG. 13C illustrates that the percentage of time spent in NREMsleep was higher at 2, 5, and 8 hours after dosing with Compound (1D)relative to the vehicle group. However, NREM sleep was significantlydecreased at 6 and 15 hours after dosing, when compared to the vehiclegroup. FIG. 13B illustrates that there were relatively minor effects andno significant effects on the percentage of time spent in REM sleep.There were also relatively minor effects and no significant changes inthe percentage amounts of wakefulness, REM sleep, and NREM sleep whenthe data were collected into 3 hour “time blocks” as shown in FIGS.14A-14C, respectfully. Collectively, these data suggested that theadministration of a single 10 mg/kg dose of Compound (1D) had minorsleep-enhancing effects in rats.

At a 100 mg/kg dose of Compound (1D), FIG. 15A illustrates that thepercentage of time spent in wakefulness was significantly decreased at 3and 5 hours after dosing during the lights-out period and at 17 hoursafter dosing during the lights-on period, when compared to the vehiclegroup. FIG. 15C illustrates that the percentage of time spent in NREMsleep was significantly increased at 3, 4, 5, and 7 hours after dosingduring the lights-out period and at 17 and 18 hours after dosing duringthe lights-on period, when compared to the vehicle group. FIG. 15Billustrates that there were relatively minor effects and no significanteffects on the percentage of time spent in REM sleep. Comparablesignificant changes in the percentage amounts of wakefulness and NREMsleep were evident when the data were collected into 3 hour blocks asshown in FIGS. 16A and 16C, respectfully—significant increases inwakefulness at from 0-3, 3-6, and 15-18 hours and significant decreasesin NREM sleep at from 0-3, 3-6, 6-9, and 15-18 hours. FIG. 16Billustrates that there were relatively minor effects and no significanteffects on the percentage of time spent in REM sleep. Collectively,these data demonstrated that the administration of a single 100 mg/kgdose of Compound (1D) had significant sleep-enhancing effects in ratsespecially during the lights-out period.

At a 10 mg/kg dose of zolpidem, FIG. 17A illustrates that the percentageof time spent in wakefulness was significantly decreased at 1 and 10hours after dosing during the lights-out period—about 46% and 43%,respectively—when each is compared to the vehicle group (about 79% and71%, respectively). Additionally, the percentage of time spent inwakefulness significantly increased at 15 hours after dosing during thelights-on period—about 69%—when compared to the vehicle group (about51%). FIG. 17C illustrates that the percentage of time spent in NREMsleep was significantly increased during the lights-out period at 1 hourafter dosing and significantly decreased during the lights-on period at15 hours after dosing—about 53% and 30%, respectively—when compared tothe vehicle group (about 18% and 47%, respectively). FIG. 17Billustrates that there were relatively minor effects and no significanteffects on the percentage of time spent in REM sleep. FIGS. 18C and 18A,respectively, where the data were collected into 3 hour blocks, confirmthe significant increase in NREM sleep at 0-3 hours after dosing andillustrate a decreased tendency in wakefulness over the period between0-12 hours after administration, when compared to the vehicle group.FIG. 18B illustrates that there were relatively minor effects and nosignificant effects on the percentage of time spent in REM sleep.Collectively, these results demonstrated that a single zolpidem dose of10 mg/kg provided a sleep-enhancing effect and induced sleep during thelights-out period. These results also demonstrated that the experimentsperformed under these conditions were sufficiently sensitive to detectthe sleep-enhancing effects of Compound (1D) in rats.

6.16 Example 16: Safety Factor of Compound (1D)

Example 13 demonstrated that, because there were no effects on thegeneral physical condition or behavior of rats even at a dose of up to600 mg/kg, the NOAEL of Compound (1D) was at least 600 mg/kg. Incontrast to Example 15, which showed a 10 mg/kg dose of Compound (1D)had minor sleep-enhancing effects, Example 14 demonstrated that Compound(1D) was effective in mitigating insomnia/inducing NREM sleep at a doseof 30 mg/kg. From the data provided by these examples, it can bedetermined that the safety factor for Compound (1D) is at least 20 fold,i.e., (>600 mg/kg)/30 mg/kg.

6.17 Example 17: Binding Efficacy and Activity Response of Compounds(1C), 405, and W-212393

The binding efficacy, K_(i), of Compound (1C) or 405, the free acid andfree base forms of these compounds, to the ORL-1, mu-opioid,kappa-opioid, and delta-opioid receptors was determined in Example 18 ofU.S. Pat. No. 8,476,271 by radioligand dose-displacement assays.Similarly, the binding efficacy of Compound W-212393, the free base formof this compound, to the ORL-1 receptor was determined according to theprocedures provided in Example 18 of U.S. Pat. No. 8,476,271 and in theExamples therein to which it refers, all of which are herebyincorporated by reference in their entirety. The binding efficacyresults are summarized in Table 20.

TABLE 20 Efficacy of Receptor Binding K_(i) (nM) [Average ± SD] OpioidReceptor Test Substance ORL-1 Mu Kappa Delta Compound (1C) 2.4 ± 0.21631 ± 77 2280 ± 213 4763 ± 509 Compound 405 1.1 ± 0.1  61.6 ± 8.7  75.4± 7.8  691 ± 57 Compound 0.7 ± 0.1 ND ND ND W-212393 ND = Not determined

The activity response of Compounds (1C) and 405 to the ORL-1, mu-opioid,and kappa-opioid receptors was determined in Example 18 of U.S. Pat. No.8,476,271 by functional [³⁵S]GTPγS binding assays. Similarly, theactivity response of Compound W-212393 to the ORL-1 receptor wasdetermined according to the procedures provided in Example 18 of U.S.Pat. No. 8,476,271 and in the Examples therein to which it refers, allof which are hereby incorporated by reference in their entirety. Theactivity response results are summarized in Table 21.

TABLE 21 Activity Response GTPγS (EC₅₀: nM, Emax: %) [Mean ± StandardError of the Mean] Opioid Receptor Test ORL-1 Mu Kappa Substance EC₅₀E_(max) EC₅₀ E_(max) EC₅₀ E_(max) Compound 4.03 ± 0.86  47.8 ±1.3 >20,000 0 >20,000 3.0 ± 0.6 (1C) Compound 0.55 ± 0.1   47.5 ±3.5 >20,000 0 >20,000 0 405 Compound 2.04 ± 0.14 102.7 ± 0.3 ND ND ND NDW-212393 ND = Not determined

It can be noted from the ORL-1 E_(max) results in Table 21 thatCompounds (1C) and 405, with values of about 47-48%, are each partialagonists. In contrast, Compound W-212393, having an E_(max) of about103%, is an agonist, i.e., a full agonist.

6.18 Example 18: In Vivo Plasma Concentration in of Compound (1D) inHumans

The plasma concentration of Compound (1D) was evaluated in humans for upto 36 hours after administration of a single oral dose of 3, 10, or 30mg of Compound (1D) in the form of a methyl cellulose suspension. Fourhealthy male subjects were administered each dose.

FIG. 19A provides a plot of the human plasma concentration of Compound(1D) on a linear scale versus linear time in hours at each dose: 3, 10,and 30 mg. FIG. 19B provides the same results in a plot of human plasmaconcentration of Compound (1D) on a logarithmic scale versus linear timeat each dose. The target plasma exposure indicated in FIG. 19A relatesto the effective dose in 80% of subjects from rat modeling results.

The pharmacokinetic information obtained from such plots is summarizedin Table 22 below, where AUC_(t) represents the area under the curvedetermined from the time of administration to the final scheduledsampling time point where the an increase in the area was measurable(i.e., 12 h at the 3 mg dose, 18 hours for 3 of the 4 subjects at the 10mg dose (12 h for the other subject), and 18 h at the 30 mg dose);AUC_(inf) represents the area under the curve determined from the timeof administration to an extrapolation to infinite time; C_(max) is themaximum plasma concentration of Compound (1D); t_(max) is the time atwhich C_(max) is achieved; t_(1/2) is the half-life; and CV % is thecoefficient of variation in percent.

TABLE 22 Pharmacokinetic Summary Statistics for Human Administration ofCompound (1D) Compound (1D) Dose 3 mg 10 mg 30 mg AUC_(t) (ng h/mL) Mean154 438 505 SD 14 107 140 Minimum 135 300 388 Maximum 168 550 708 CV %9.1 24 28 AUC_(inf) (ng h/mL) Mean 161 447 512 SD 14 101 139 Minimum 144320 398 Maximum 176 557 714 CV % 8.7 23 27 C_(max) (ng/mL) Mean 30 77 83SD 5 17 17 Minimum 23 56 69 Maximum 34 98 106 CV % 17 22 21 t_(max)(hours) Mean 1.6 1.5 1.8 SD 0.25 0.4 1.0 Minimum 1.5 1.0 1.0 Median 1.51.5 1.5 Maximum 2.0 2.0 3.0 t_(1/2) (hours) Mean 2.3 2.6 2.8 SD 0.3 0.30.3 Minimum 2.1 2.4 2.6 Maximum 2.6 3.0 3.2

The results in Table 22 demonstrate that there was rapidgastrointestinal absorption of Compound (1D) across the three doses. Inparticular, the mean t_(max) was similar across the three doses, i.e.,1.6, 1.5 and 1.8 hours, and ranged from a minimum of about 1 hour to amaximum of about 3 hours. The results in Table 22 also demonstrate thatthere was a short terminal elimination half-life. In particular, themean t_(1/2) was short and similar across the three doses, i.e., 2.3,2.6 and 2.8 hours, and ranged from a minimum of about 2.1 hours to amaximum of about 3.2 hours.

6.19 Example 19: In Vivo Clearance of Radiolabeled Compound (1D) inAnimals

The clearance of Compound (1D) from rats, dogs, and monkeys wasdetermined by analyzing excreta samples from the animals (and controlsas required) for a radiolabeled form of the compound.

Specifically, liquid scintillation counting (“LSC”) was used for thedetermination of total radiolabeled Compound (1D) material, i.e., theoriginal or parent compound and its metabolites. The radiolabeledCompound (1D) that was synthesized comprised ¹⁴C as a phenyl groupcarbon atom of the quinoxaline skeleton of the molecule and is denotedherein as [¹⁴C]-Compound (1D). Using ¹⁴C as a radiolabel forpharmacokinetic studies is a recognized technique and embedding theradiolabel into the ring structure was done to limit migration orexchange of the radiolabel to non-Compound (1D)-related molecules. Thespecific radioactivity for the lot of [¹⁴C]-Compound (1D) synthesizedwas 2.50 MBq/mg (67.6 μCi/mg) [3.49 MBq/mg (94.4 μCi/mg) if the materialwere to be present as the free base form] with a radiochemical purity ofgreater than 98.5% as determined by HPLC. The synthesized radiolabeled[¹⁴C]-Compound (1D) was stored away from light at a temperature of −80°C. before use.

Following oral administration of [¹⁴C]-Compound (1D) (in an appropriatevehicle, e.g., a methyl cellulose suspension) to the experimentalanimals, excreta samples were collected over specified time intervals.Urine samples were collected at fixed intervals post dosing. Fecalsamples were homogenized and diluted prior to being solubilized.Aliquots of these samples were counted following the addition of liquidscintillation fluid thereto. Detection limits for radioactivity in theexcreta samples were set at twice the background count (from blanksamples) as determined by LSC. The [¹⁴C]-Compound (1D) was stable forabout 4-5 hours in urine at a temperature of about 25° C. and, when keptrefrigerated at 4° C., for up to 15 days (rat urine) and 36 days (dogurine). Recovery of [¹⁴C]-Compound (1D) from rat urine was typicallyfrom about 91.6 to about 99.1%. Recovery of [¹⁴C]-Compound (1D) from dogurine was typically from about 100.9 to about 105.0%.

Oral doses of [¹⁴C]-Compound (1D) given to rats were rapidly absorbed,widely distributed, and rapidly eliminated. The organs with the highest[¹⁴C]-Compound (1D) burden following oral dosing of rats were the liverand kidney. However, it should be noted from Example 8 herein thatalthough the radiolabeled compound appeared in rat livers because of thehigh blood flow therein, the non-radiolabeled Compound (1F) wasnegligibly metabolized by either rat liver microsomes or human livermicrosomes. Only trace levels (below the limit of quantification) of[¹⁴C]-Compound (1D)-derived radioactivity were found in any rat tissues72 hours post dose.

There were no major metabolites of [¹⁴C]-Compound (1D) detected in allspecies tested. Only a few minor metabolites were identified by highperformance liquid chromatography with tandem mass spectrometrydetection (“HPLC-MS-MS”) in animal bile, urine, and feces. Thesemetabolites were the 6-hydroxide, the 1-hydroxide, the decarboxylate,and the +2 form of [¹⁴C]-Compound (1D).

In a one week study, the elimination of [¹⁴C]-Compound (1D) was largelythrough feces in male rats and monkeys but through both the urine andfeces in dogs; Table 23 below provides a summary of the results wherethe average % elimination is determined from the average of the ratio ofthe recovered ¹⁴C amount to amount of ¹⁴C administered as [¹⁴C]-Compound(1D).

TABLE 23 % Elimination of [¹⁴C]-Compound (1D)-Derived RadioactivityWithin 168 Hours of Oral Dosing Average % Elimination Elimination RatMonkey Dog Route (male) ^(a) (female) (male) Fecal ^(b) 84.1 81.3 46.3Urinary 14.9 20.7 50.3 Fecal + Urinary 99.0 102.0 96.6 ^(a) Renal drugclearance in female rats is about twice that of males. ^(b) Includesunabsorbed and biliary excreted drug.In a shorter duration study, female rats eliminated more of Compound(1D) via the urine than male rats; Table 24 below summarizes theseresults.

TABLE 24 % Elimination of Compound (1D)-Derived Radioactivity Within 48Hours of Oral Dosing Average % Elimination Elimination Route Rat (male)Rat (female) Fecal 41.6 27.9 Urinary 54.4 66.8 Fecal + Urinary 96.0 94.7However, it should be noted from the data in Table 24 that the totalamount eliminated was substantially identical for male and female rats.

As can be noted from this example, the total average % elimination wasextremely high for all species tested, ranging from a low value of about95% to essentially 100%. In summary, as is evident from the results inthis example, [¹⁴C]-Compound (1D) was poorly metabolized in vivo in allanimal species tested.

6.20 Example 20: In Vivo Renal Clearance of Compound (1D) in Humans

The renal clearance of Compound (1D) was evaluated in humans for up to36 hours after administration of a single oral dose of 3, 10, or 30 mgof Compound (1D) in the form of a methyl cellulose suspension. Fourhealthy male subjects were administered each dose. Table 25 belowprovides the results in the form of the mean renal clearance, mean totalamount excreted unchanged ad Compound (1D), and mean percentage doseexcreted unchanged.

TABLE 25 Renal Clearance and Elimination of Compound (1D) Mean RenalMean Total Mean % Dose Dose Clearance Amount Excreted Excreted (mg)(mL/minute) Unchanged (mg) Unchanged 3.0 275 2.66 89 10 266 6.95 70 30270 8.37 28

The results in Table 25 demonstrated that Compound (1D) was excretedlargely unchanged in human urine. Additionally, there was active renaltubular secretion in addition to glomerular filtration. In particular, a3 mg oral dose of Compound (1D) was essentially completely absorbed froman aqueous suspension from the gastrointestinal tract and, for the 3 and10 mg doses, there was relatively rapid absorption and elimination ofCompound (1D).

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims. A number of referenceshave been cited, the entire disclosures of which are incorporated hereinby reference for all purposes.

What is claimed:
 1. A method for treating or preventing a sleepdisorder, comprising administering to an animal in need thereof atherapeutically effective amount of a compound of Formula (1)

or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the compound is a compound of Formula (1A)

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the compound is a compound of Formula (1B)

or a pharmaceutically acceptable salt thereof.
 4. The method of claim 1,wherein the compound is a compound of Formula (1C)

or a pharmaceutically acceptable salt thereof.
 5. The method of claim 4,wherein the compound is a compound of Formula (1D)


6. The method of claim 4, wherein the compound is a compound of Formula(1E)


7. The method of claim 4, wherein the compound is a compound of Formula(1F)


8. The method of any one of claims 1-7, wherein the sleep disorder is aninsomnia condition, a hypersomnia condition, a circadian rhythmsleep-wake disorder, an alcohol-induced sleep disorder, or anycombination thereof.
 9. The method of claim 8, wherein thealcohol-induced sleep disorder is insomnia-type alcohol-induced sleepdisorder, daytime sleepiness type alcohol-induced sleep disorder,parasomnia type alcohol-induced sleep disorder, mixed typealcohol-induced sleep disorder, insomnia in alcohol use disorder, asleep disorder associated with alcohol cessation, insomnia associatedwith alcohol cessation, or any combination thereof.
 10. The method ofclaim 8 or 9, wherein the alcohol-induced sleep disorder is treated. 11.The method of claim 8 or 9, wherein the alcohol-induced sleep disorderis prevented.
 12. The method of claim 8, wherein the insomnia conditionis insomnia, child insomnia, middle-of-the-night insomnia, short sleeperdisorder, or any combination thereof.
 13. The method of claim 8 or 12,wherein the insomnia condition is treated.
 14. The method of claim 8 or12, wherein the insomnia condition is prevented.
 15. The method of claim8, wherein the hypersomnia condition is insufficient sleep syndrome. 16.The method of claim 8 or 15, wherein the hypersomnia condition istreated.
 17. The method of claim 8 or 15, wherein the hypersomniacondition is prevented.
 18. The method of claim 8, wherein the circadianrhythm sleep-wake disorder is delayed sleep-wake phase, advancedsleep-wake phase, irregular sleep-wake rhythm, non-24-hour sleep-wakerhythm, shift work syndrome, jet lag, or any combination thereof. 19.The method of claim 8 or 18, wherein the circadian rhythm sleep-wakedisorder is treated.
 20. The method of claim 8 or 18, wherein thecircadian rhythm sleep-wake disorder is prevented.
 21. The method of anyone of claims 1-20, wherein sleep efficiency of an animal administered asingle daily dose of the compound or a pharmaceutically acceptable saltthereof on two consecutive days is at least about 1.10 times the sleepefficiency of an animal administered a placebo.
 22. The method of anyone of claims 1-21, wherein latency to persistent sleep of an animaladministered a single daily dose of the compound or a pharmaceuticallyacceptable salt thereof on two consecutive days is at most about 0.65times the latency to persistent sleep of an animal administered aplacebo.
 23. The method of any one of claims 1-22, wherein wake aftersleep onset (WASO) of an animal administered a single daily dose of thecompound or a pharmaceutically acceptable salt thereof on twoconsecutive days is at most about 0.50 times the WASO of an animaladministered a placebo.
 24. The method of any one of claims 1-23,wherein administration of the compound or a pharmaceutically acceptablesalt thereof is by at least one route selected from oral, parenteral,intravenous, intramuscular, buccal, gingival, sublingual, intraocular,transdermal, and transmucosal.
 25. The method of claim 24, whereinadministration of the compound or pharmaceutically acceptable saltthereof is by oral, sublingual, gingival, or buccal administration. 26.The method of any one of claims 1-25, wherein the dosage of the compoundor pharmaceutically acceptable salt thereof is from about 0.003mg/kg/day to about 100 mg/kg/day based on the body weight of the animaladministered the dosage.
 27. The method of any one of claims 1-26,wherein the dosage of the compound or pharmaceutically acceptable saltthereof is from about 0.003 mg/kg/day to about 10 mg/kg/day based on thebody weight of the animal administered the dosage.
 28. The method of anyone of claims 1-27, wherein the dosage of the compound orpharmaceutically acceptable salt thereof is from about 0.003 mg/kg/dayto about 5 mg/kg/day based on the body weight of the animal administeredthe dosage.
 29. The method of any one of claims 1-28, wherein the dosageof the compound or pharmaceutically acceptable salt thereof is fromabout 0.003 mg/kg/day to about 1.0 mg/kg/day based on the body weight ofthe animal administered the dosage.
 30. The method of any one of claims1-29, wherein the dosage of the compound or pharmaceutically acceptablesalt thereof is from about 0.003 mg/kg/day to about 0.15 mg/kg/day. 31.The method of any one of claims 1-29, wherein the dosage of the compoundor pharmaceutically acceptable salt thereof is from about 0.010mg/kg/day to about 1.0 mg/kg/day.
 32. The method of any one of claims1-29, wherein the dosage of the compound or pharmaceutically acceptablesalt thereof is from about 0.010 mg/kg/day to about 0.10 mg/kg/day. 33.The method of any one of claims 1-25, wherein the single daily humandose of the compound or pharmaceutically acceptable salt thereof is fromabout 0.05 mg to about 100 mg or from about 0.05 mg to about 50 mg. 34.The method of claim 33, wherein the single daily human dose of thecompound or pharmaceutically acceptable salt thereof is from about 0.10mg to about 15 mg.
 35. The method of claim 33 or 34, wherein the singledaily human dose of the compound or pharmaceutically acceptable saltthereof is from about 0.2 mg to about 6.0 mg.
 36. The method of claims 4and 8-35, wherein the free base of the compound of Formula (1C) isadministered.
 37. The method of claims 4 and 8-35, wherein apharmaceutically acceptable salt of the compound of Formula (1C) isadministered.
 38. The method of any one of claim 37, wherein thepharmaceutically acceptable salt is a hydrochloric acid salt, ap-toluenesulfonic acid salt, a sulfate salt, or a phosphoric acid salt.39. The method of claim 37, wherein the pharmaceutically acceptable saltis a p-toluenesulfonic acid salt.
 40. The method of claim 39, whereinthe pharmaceutically acceptable salt is the mono-tosylate salt.
 41. Useof the compound or a pharmaceutically acceptable salt thereof as definedin any one of claims 1-7 or claims 36-40 in the preparation of amedicament for the treatment or prevention of a sleep disorder.
 42. Theuse of claim 41, wherein a sleep disorder is treated.
 43. The use ofclaim 41, wherein a sleep disorder is prevented.
 44. The use of any oneof claims 41-43, wherein the sleep disorder is an insomnia condition, ahypersomnia condition, a circadian rhythm sleep-wake disorder, analcohol-induced sleep disorder, or any combination thereof.
 45. The useof claim 44, wherein the sleep disorder is an alcohol-induced sleepdisorder which is insomnia-type alcohol-induced sleep disorder, daytimesleepiness type alcohol-induced sleep disorder, parasomnia typealcohol-induced sleep disorder, mixed type alcohol-induced sleepdisorder, insomnia in alcohol use disorder, a sleep disorder associatedwith alcohol cessation, insomnia associated with alcohol cessation, orany combination thereof.
 46. The use of claim 45, wherein thealcohol-induced sleep disorder is insomnia-type alcohol-induced sleepdisorder.
 47. The use of claim 45, wherein the alcohol-induced sleepdisorder is daytime sleepiness type alcohol-induced sleep disorder. 48.The use of claim 45, wherein the alcohol-induced sleep disorder isparasomnia type alcohol-induced sleep disorder.
 49. The use of claim 45,wherein the alcohol-induced sleep disorder is mixed type alcohol-inducedsleep disorder.
 50. The use of claim 45, wherein the alcohol-inducedsleep disorder is insomnia in alcohol use disorder.
 51. The use of claim45, wherein the alcohol-induced sleep disorder is a sleep disorderassociated with alcohol cessation.
 52. The use of claim 45, wherein thealcohol-induced sleep disorder is insomnia associated with alcoholcessation.
 53. The use of claim 44, wherein the sleep disorder is aninsomnia condition which is insomnia, child insomnia,middle-of-the-night insomnia, short sleeper disorder, or any combinationthereof.
 54. The use of claim 53, wherein the insomnia condition isinsomnia.
 55. The use of claim 53, wherein the insomnia condition ischild insomnia.
 56. The use of claim 53, wherein the insomnia conditionis middle-of-the-night insomnia.
 57. The use of claim 53, wherein theinsomnia condition is short sleeper disorder.
 58. The use of claim 44,wherein the sleep disorder is a hypersomnia condition which isinsufficient sleep syndrome.
 59. The use of claim 44, wherein the sleepdisorder is a circadian rhythm sleep-wake disorder which is delayedsleep-wake phase, advanced sleep-wake phase, irregular sleep-wakerhythm, non-24-hour sleep-wake rhythm, shift work syndrome, jet lag, orany combination thereof.
 60. The use of claim 59, wherein the circadianrhythm sleep-wake disorder is delayed sleep-wake phase.
 61. The use ofclaim 59, wherein the circadian rhythm sleep-wake disorder is advancedsleep-wake phase.
 62. The use of claim 59, wherein the circadian rhythmsleep-wake disorder is irregular sleep-wake rhythm.
 63. The use of claim59, wherein the circadian rhythm sleep-wake disorder is non-24-hoursleep-wake rhythm.
 64. The use of claim 59, wherein the circadian rhythmsleep-wake disorder is shift work syndrome.
 65. The use of claim 59,wherein the circadian rhythm sleep-wake disorder is jet lag.
 66. Apharmaceutical composition for treating or preventing a sleep disorder,comprising the compound or a pharmaceutically acceptable salt thereof asdefined in any one of claims 1-7 and 36-40.
 67. The pharmaceuticalcomposition of claim 66, wherein the sleep disorder is an insomniacondition, a hypersomnia condition, a circadian rhythm sleep-wakedisorder, an alcohol-induced sleep disorder, or any combination thereof.68. The pharmaceutical composition of claim 67, wherein thealcohol-induced sleep disorder is insomnia-type alcohol-induced sleepdisorder, daytime sleepiness type alcohol-induced sleep disorder,parasomnia type alcohol-induced sleep disorder, mixed typealcohol-induced sleep disorder, insomnia in alcohol use disorder, asleep disorder associated with alcohol cessation, insomnia associatedwith alcohol cessation, or any combination thereof.
 69. Thepharmaceutical composition of claim 67 or 68, wherein thealcohol-induced sleep disorder is treated.
 70. The pharmaceuticalcomposition of claim 67 or 68, wherein the alcohol-induced sleepdisorder is prevented.
 71. The pharmaceutical composition of claim 66 or67, wherein the sleep disorder is an insomnia condition, a hypersomniacondition, a circadian rhythm sleep-wake disorder, or any combinationthereof.
 72. The pharmaceutical composition of claim 67 or 71, whereinthe insomnia condition is insomnia, child insomnia, middle-of-the-nightinsomnia, short sleeper disorder, or any combination thereof.
 73. Thepharmaceutical composition of claim 67, 71 or 72, wherein the insomniacondition is treated.
 74. The pharmaceutical composition of claim 67, 71or 72, wherein the insomnia condition is prevented.
 75. Thepharmaceutical composition of claim 67 or 71, wherein the hypersomniacondition is insufficient sleep syndrome.
 76. The pharmaceuticalcomposition of claim 67, 71 or 75, wherein the hypersomnia condition istreated.
 77. The pharmaceutical composition of claim 67, 71 or 75,wherein the hypersomnia condition is prevented.
 78. The pharmaceuticalcomposition of claim 67 or 71, wherein the circadian rhythm sleep-wakedisorder is delayed sleep-wake phase, advanced sleep-wake phase,irregular sleep-wake rhythm, non-24-hour sleep-wake rhythm, shift worksyndrome, jet lag, or any combination thereof.
 79. The pharmaceuticalcomposition of claim 67, 71 or 78, wherein the circadian rhythmsleep-wake disorder is treated.
 80. The pharmaceutical composition ofclaim 67, 71 or 78, wherein the circadian rhythm sleep-wake disorder isprevented.
 81. The pharmaceutical composition of any one of claims66-80, wherein the composition further comprises a pharmaceuticallyacceptable carrier or excipient.
 82. A compound as defined in any one ofclaims 1-7 and 36-40 or a pharmaceutically acceptable salt thereof foruse in treating or preventing a sleep disorder.
 83. The compound for useof claim 82, wherein the sleep disorder is an insomnia condition, ahypersomnia condition, a circadian rhythm sleep-wake disorder, analcohol-induced sleep disorder, or any combination thereof.
 84. Thecompound for use of claim 83, wherein the alcohol-induced sleep disorderis insomnia-type alcohol-induced sleep disorder, daytime sleepiness typealcohol-induced sleep disorder, parasomnia type alcohol-induced sleepdisorder, mixed type alcohol-induced sleep disorder, insomnia in alcoholuse disorder, a sleep disorder associated with alcohol cessation,insomnia associated with alcohol cessation, or any combination thereof.85. The compound for use of claim 83 or 84, wherein the alcohol-inducedsleep disorder is treated.
 86. The compound for use of claim 83 or 84,wherein the alcohol-induced sleep disorder is prevented.
 87. Thecompound for use of claim 82 or 83, wherein the sleep disorder is aninsomnia condition, a hypersomnia condition, a circadian rhythmsleep-wake disorder, or any combination thereof.
 88. The compound foruse of claim 83 or 87, wherein the insomnia condition is insomnia, childinsomnia, middle-of-the-night insomnia, short sleeper disorder, or anycombination thereof.
 89. The compound for use of claim 83, 87 or 88,wherein the insomnia condition is treated.
 90. The compound for use ofclaim 83, 87 or 88, wherein the insomnia condition is prevented.
 91. Thecompound for use of claim 83 or 87, wherein the hypersomnia condition isinsufficient sleep syndrome.
 92. The compound for use of claim 83, 87 or91, wherein the hypersomnia condition is treated.
 93. The compound foruse of claim 83, 87 or 91, wherein the hypersomnia condition isprevented.
 94. The compound for use of claims 83 and 87, wherein thecircadian rhythm sleep-wake disorder is delayed sleep-wake phase,advanced sleep-wake phase, irregular sleep-wake rhythm, non-24-hoursleep-wake rhythm, shift work syndrome, jet lag, or any combinationthereof.
 95. The compound for use of claim 83, 87 or 94, wherein thecircadian rhythm sleep-wake disorder is treated.
 96. The compound foruse of claim 83, 87 or 94, wherein the circadian rhythm sleep-wakedisorder is prevented.